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Journal articles on the topic 'CUG'

Author: Grafiati
Published: 4 June 2021
Last updated: 17 February 2022

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1

Tamjar, Jevgenia, Elizaveta Katorcha, Alexander Popov, and Lucy Malinina. "Structural dynamics of double-helical RNAs composed of CUG/CUG- and CUG/CGG-repeats." Journal of Biomolecular Structure and Dynamics 30, no. 5 (September 2012): 505–23. http://dx.doi.org/10.1080/07391102.2012.687517.

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2

Reddy, Kaalak, Jana R. Jenquin, Ona L. McConnell, John D. Cleary, Jared I. Richardson, Belinda S. Pinto, Maja C. Haerle, et al. "A CTG repeat-selective chemical screen identifies microtubule inhibitors as selective modulators of toxic CUG RNA levels." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 20991–1000. http://dx.doi.org/10.1073/pnas.1901893116.

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A CTG repeat expansion in the DMPK gene is the causative mutation of myotonic dystrophy type 1 (DM1). Transcription of the expanded CTG repeat produces toxic gain-of-function CUG RNA, leading to disease symptoms. A screening platform that targets production or stability of the toxic CUG RNA in a selective manner has the potential to provide new biological and therapeutic insights. A DM1 HeLa cell model was generated that stably expresses a toxic r(CUG)480 and an analogous r(CUG)0 control from DMPK and was used to measure the ratio-metric level of r(CUG)480 versus r(CUG)0. This DM1 HeLa model recapitulates pathogenic hallmarks of DM1, including CUG ribonuclear foci and missplicing of pre-mRNA targets of the muscleblind (MBNL) alternative splicing factors. Repeat-selective screening using this cell line led to the unexpected identification of multiple microtubule inhibitors as hits that selectively reduce r(CUG)480 levels and partially rescue MBNL-dependent missplicing. These results were validated by using the Food and Drug Administration-approved clinical microtubule inhibitor colchicine in DM1 mouse and primary patient cell models. The mechanism of action was found to involve selective reduced transcription of the CTG expansion that we hypothesize to involve the LINC (linker of nucleoskeleton and cytoskeleton) complex. The unanticipated identification of microtubule inhibitors as selective modulators of toxic CUG RNA opens research directions for this form of muscular dystrophy and may shed light on the biology of CTG repeat expansion and inform therapeutic avenues. This approach has the potential to identify modulators of expanded repeat-containing gene expression for over 30 microsatellite expansion disorders.
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3

Angelbello, Alicia J., Suzanne G. Rzuczek, Kendra K. Mckee, Jonathan L. Chen, Hailey Olafson, Michael D. Cameron, Walter N. Moss, Eric T. Wang, and Matthew D. Disney. "Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model." Proceedings of the National Academy of Sciences 116, no. 16 (March 29, 2019): 7799–804. http://dx.doi.org/10.1073/pnas.1901484116.

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Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG)exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.
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4

Lee, Johanna E., and Thomas A. Cooper. "Pathogenic mechanisms of myotonic dystrophy." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1281–86. http://dx.doi.org/10.1042/bst0371281.

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DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.
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5

Jasinska, Anna J., Piotr Kozlowski, and Wlodzimierz J. Krzyzosiak. "Expression characteristics of triplet repeat-containing RNAs and triplet repeat-interacting proteins in human tissues." Acta Biochimica Polonica 55, no. 1 (January 30, 2008): 1–8. http://dx.doi.org/10.18388/abp.2008_3090.

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Numerous human transcripts contain tandem repeats of trinucleotide motifs, the function of which remains unknown. In this study we used the available gene expression EST data to characterize the abundance of a large group of these transcripts in different tissues and determine the mRNAs which had the highest contribution to the observed levels of transcripts containing different types of the CNG repeats. A more extensive characteristics was performed for transcripts containing the CUG repeats, and those encoding the repeat-binding proteins. The scarcity of double-stranded CUG repeats as well as various proportions of the single-stranded and double-stranded CUG repeat-binding proteins were revealed in the studied transcriptomes. The observed correlated levels of transcripts containing single-stranded CUG repeats and of proteins binding single-stranded CUG repeats may imply that in addition to transcripts which only provide binding sites for these proteins there may be a substantial portion of the transcripts whose metabolism is directly regulated by such proteins. Our results showing a highly variable composition of triplet repeat-containing transcripts and their interacting proteins in different tissues may contribute to a better understanding of the mechanism of RNA-mediated pathogenesis in triplet repeat expansion diseases.
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6

Peng, Shaohong, Pei Guo, Xiao Lin, Ying An, Kong Hung Sze, Matthew Ho Yan Lau, Zhefan Stephen Chen, et al. "CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration." Proceedings of the National Academy of Sciences 118, no. 19 (May 4, 2021): e2022940118. http://dx.doi.org/10.1073/pnas.2022940118.

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DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington’s disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.
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7

Chang, Elizabeth T., James M. Donahue, Lan Xiao, Yuhong Cui, Jaladanki N. Rao, Douglas J. Turner, William S. Twaddell, Jian-Ying Wang, and Richard J. Battafarano. "The RNA-binding protein CUG-BP1 increases survivin expression in oesophageal cancer cells through enhanced mRNA stability." Biochemical Journal 446, no. 1 (July 27, 2012): 113–23. http://dx.doi.org/10.1042/bj20120112.

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Survivin, a member of the IAP (inhibitor of apoptosis protein) family, plays important roles in maintaining cellular homoeostasis and regulating cell-cycle progression. This IAP is overexpressed in oesophageal cancer cells, leading to uncontrolled cell growth and resistance to apoptosis. CUG-BP1 (CUG-binding protein 1) is an RNA-binding protein that regulates the stability and translational efficiency of target mRNAs. In the present paper, we report that CUG-BP1 is overexpressed in oesophageal cancer cell lines and human oesophageal cancer specimens. CUG-BP1 associates with the 3′-untranslated region of survivin mRNA, thereby stabilizing the transcript and elevating its expression in oesophageal cancer cells. Our results show that overexpression of CUG-BP1 in oesophageal epithelial cells results in increased survivin mRNA stability and consequently survivin protein expression. Conversely, silencing CUG-BP1 in oesophageal cancer cells destabilizes survivin mRNA, lowering the level of survivin protein. In addition, we have found that altering CUG-BP1 expression modulates susceptibility to chemotherapy-induced apoptosis. Overexpression of CUG-BP1 in oesophageal epithelial cells increases resistance to apoptosis, whereas silencing CUG-BP1 makes oesophageal cancer cells more susceptible to chemotherapy-induced apoptosis. Co-transfection experiments with small interfering RNA directed against survivin suggest that the anti-apoptotic role for CUG-BP1 is not entirely dependent on its effect on survivin expression.
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8

Sha, Zongyao, Yahya Ali, Yuwei Wang, Jiangping Chen, Xicheng Tan, and Ruren Li. "Mapping the Changes in Urban Greenness Based on Localized Spatial Association Analysis under Temporal Context Using MODIS Data." ISPRS International Journal of Geo-Information 7, no. 10 (October 13, 2018): 407. http://dx.doi.org/10.3390/ijgi7100407.

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Vegetation plays an irreplaceable role for urban ecosystem services. Urban greenness represents all vegetation cover in and around cities. Understanding spatiotemporal patterns of the changes in urban greenness (CUG) provides fundamental clues for urban planning. The impact on CUG can be roughly categorized as being climate-induced and human-induced. Methods for mapping human-induced CUG (H-CUG) are rare. In this paper, a new framework, known as Localized Spatial Association Analysis under Temporal Context (LSAA-TC), was proposed to explore H-CUG. Localized spatial association analysis (LSAA) was performed first to extract local spatial outliers (LSOs), or locations that differ significantly in urban greenness from those located in the neighborhood. LSOs were then analyzed under the temporal context to map their intertemporal variations known as spatiotemporal outliers. We applied LSAA-TC to mapping H-CUG in the Wuhan Metropolitan Area, China during 2000–2015 using the vegetation index from Moderate-resolution Imaging Spectroradiometer (MODIS) 13Q1 as the proxy for urban greenness. The computed H-CUG demonstrated apparent spatiotemporal patterns. The result is consistent with the fact that the traditional downtown area presents the lowest H-CUG, while it is found that the peripheral area in the circular belt within 14–20 km from the urban center demonstrates the most significant H-CUG. We conclude that LSAA-TC can be a widely applicable framework to understand H-CUG patterns and is a promising tool for informative urban planning.
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9

Sun, Jinguo, Yucun Liu, Longyi Jin, Tie Chen, and Bingzhu Yin. "Coordination-induced gelation of an l-glutamic acid Schiff base derivative: the anion effect and cyanide-specific selectivity." Chemical Communications 52, no. 4 (2016): 768–71. http://dx.doi.org/10.1039/c5cc07903a.

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Three metallogels, ZnG, CuG and Zn-CuG, were prepared in the presence of specific anions, with their efficacy linked to the Hofmeister series. Importantly, Zn-CuG gel could fluorescently detect CN− with specific selectivity.
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10

Krukowski, Jakub, Adam Kałużny, Jakub Kłącz, and Marcin Matuszewski. "Comparison between cystourethrography and sonourethrography in preoperative diagnostic management of patients with anterior urethral strictures." Medical Ultrasonography 20, no. 4 (December 8, 2018): 436. http://dx.doi.org/10.11152/mu-1613.

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Aim: To evaluate the urethral lesions and the degree of spongiofibrosis using cystourethrography (CUG) and sonourethrography (SUG) in order to propose the best imaging method for further surgical treatment.Material and methods: The study involved 66 patients with anterior urethral strictures with indication for urethroplasty. Results of CUG and SUG were compared with each other and data from surgical protocol.Results: Totally 72 strictures were detected; 47 in the bulbar part of urethra and 25 in the penile urethra. The mean length of the stenosis was 16.43 mm for CUG and 27.41 mm for SUG and 31.05 mm during surgery. The correlation levels between imaging techniques and intraoperative measurements were 0.55 (p<0.001) for CUG and 0.73 (p<0.001) for SUG. After dividing the strictures according to their location, better correlation for stenoses was obtained in penile urethra: 0.66 (p<0.001) for CUG and 0.86 (p<0.001) for SUG.Conclusions: SUG seems to be a simple and fast examination to evaluate urethral strictures. It is more accurate in comparison to CUG and gives a possibility to assess the spongiofibrosis. This information suggests that SUG can be a good complement to CUG in diagnosis of anterior urethtral strictures.
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11

Polepalli, Vamsee Krishna, Venu Gopala Sarma, and Suresh Reddy D. "Study of antenatal and postnatal factors affecting catchup growth in intrauterine growth retarded babies during first year." International Journal of Contemporary Pediatrics 6, no. 2 (February 23, 2019): 621. http://dx.doi.org/10.18203/2349-3291.ijcp20190699.

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Background: The burden of IUGR is concentrated mainly in Asia with the proportion of IUGR 54% in India. Higher rates of IUGR should be a cause of concern because they signal high risk of malnutrition, morbidity and mortality for the new born. This study was done to see the factors affecting catchup growth (CUG) of IUGR babies during first year.Methods: The study was done in 120 SGA babies for a period of 18 months from October 2013 to March 2015. Antenatal, postnatal factors and anthropometry at 1st, 2nd, 3rd, 6th, 9th and 12 months were noted and analysed.Results: 78.3% babies showed CUG with in the first year. Preterm IUGR infants showed better CUG than full term. Asymmetric IUGR infants showed better CUG than symmetric. Teenage pregnancy, hypertensive disorders, multiple pregnancies, cardiac disease, anemia, type of IUGR, NICU stay, type of feeding, socioeconomic status, mother age, mother height, mother hemoglobin, gestational age, multiple gestation, birth weight, birth length, head circumference at birth all influenced CUG.Conclusions: Teenage pregnancies should be avoided. In SGA babies of pregnancy induced hypertension and preeclampsia, failure in CUG occurred more, these babies need to be followed in high risk clinics. SGA infants of mothers with low haemoglobin failed to show CUG, so antenatal nutrition improvement of mother should be done. Breastfed babies had higher CUG rates than formula fed babies, so exclusive breastfeeding should be promoted.
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12

Marquis, Julien, Luc Paillard, Yann Audic, Bertrand Cosson, Olivier Danos, Christine Le Bec, and H. Beverley Osborne. "CUG-BP1/CELF1 requires UGU-rich sequences for high-affinity binding." Biochemical Journal 400, no. 2 (November 14, 2006): 291–301. http://dx.doi.org/10.1042/bj20060490.

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CUG-BP1 [CUG-binding protein 1 also called CELF (CUG-BP1 and ETR3 like factors) 1] is a human RNA-binding protein that has been implicated in the control of splicing and mRNA translation. The Xenopus homologue [EDEN-BP (embryo deadenylation element-binding protein)] is required for rapid deadenylation of certain maternal mRNAs just after fertilization. A variety of sequence elements have been described as target sites for these two proteins but their binding specificity is still controversial. Using a SELEX (systematic evolution of ligand by exponential enrichment) procedure and recombinant CUG-BP1 we selected two families of aptamers. Surface plasmon resonance and electrophoretic mobility-shift assays showed that these two families differed in their ability to bind CUG-BP1. Furthermore, the selected high-affinity aptamers form two complexes with CUG-BP1 in electrophoretic mobility assays whereas those that bind with low affinity only form one complex. The validity of the distinction between the two families of aptamers was confirmed by a functional in vivo deadenylation assay. Only those aptamers that bound CUG-BP1 with high affinity conferred deadenylation on a reporter mRNA. These high-affinity RNAs are characterized by a richness in UGU motifs. Using these binding site characteristics we identified the Xenopus maternal mRNA encoding the MAPK (mitogen-activated protein kinase) phosphatase (XCl100α) as a substrate for EDEN-BP. In conclusion, high-affinity CUG-BP1 binding sites are sequence elements at least 30 nucleotides in length that are enriched in combinations of U and G nucleotides and contain at least 4 UGU trinucleotide motifs. Such sequence elements are functionally competent to target an RNA for deadenylation in vivo.
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13

RAJKOWSKI, Kamil, and Tomasz MAJEWSKI. "Testing of Sinters Made of Copper Powders Coated with Carbon Structure Containing Graphene." Problems of Mechatronics Armament Aviation Safety Engineering 12, no. 2 (June 30, 2021): 75–90. http://dx.doi.org/10.5604/01.3001.0014.9339.

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This paper presents the results of preliminary tests on specimens made from mixtures of dendritic copper powder (CuE) with the graphene-coated copper powder (CuG) in a range from 20% to 100% (CuG). The properties of the powder mixtures, green compacts and sinters were determined. To study the properties of the powder mixtures, the following tests were carried out: a measurement of the CuG powder grain size after the grinding process, measurements of the bulk density and tap density of the prepared powder mixtures. The porosity of the produced green compacts and the sinters was calculated as well as the densification capabilities of the powder mixtures by die pressing, cold isostatic pressing and sintering in a reducing atmosphere were tested. Moreover, the nature of the porosity formation was analysed using an optical microscope and the Brinell hardness was determined. The measured Brinell hardness was in the range of 17 HB for sinters made from CuG to 34 HB for sinters made from a 20% CuG powder mixture. More than six hundred measurements that were made in this study show that the high CuG content in the powder mixture reduce the hardness of the sinters as well increase their porosity.
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14

Jukes, T. H., and S. Osawa. "CUG codons inCandida spp." Journal of Molecular Evolution 42, no. 2 (February 1996): 321–22. http://dx.doi.org/10.1007/bf02198859.

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15

Pesole, G., M. Lotti, L. Alberghina, and C. Saccone. "Evolutionary origin of nonuniversal CUGSer codon in some Candida species as inferred from a molecular phylogeny." Genetics 141, no. 3 (November 1, 1995): 903–7. http://dx.doi.org/10.1093/genetics/141.3.903.

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Abstract CUG, a universal leucine codon, has been reported to be read as serine in various yeast species belonging to the genus Candida. To gain a deeper insight into the origin of this deviation from the universal genetic code, we carried out a phylogenetic analysis based on the small-subunit ribosomal RNA genes from some Candida and other related Hemiascomycetes. Furthermore, we determined the phylogenetic relationships between the tRNA(Ser)CAG, responsible for the translation of CUG, from some Candida species and the other serine and leucine isoacceptor tRNAs in C. cylindracea. We demonstrate that the group of Candida showing the genetic code deviation is monophyletic and that this deviation could have originated more than 150 million years ago. We also describe how phylogenetic analysis can be used for genetic code predictions.
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16

Vagner, S., C. Touriol, B. Galy, S. Audigier, M. C. Gensac, F. Amalric, F. Bayard, H. Prats, and A. C. Prats. "Translation of CUG- but not AUG-initiated forms of human fibroblast growth factor 2 is activated in transformed and stressed cells." Journal of Cell Biology 135, no. 5 (December 1, 1996): 1391–402. http://dx.doi.org/10.1083/jcb.135.5.1391.

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Four isoforms of the human fibroblast growth factor 2 (FGF-2), with different intracellular localizations and distinct effects on cell phenotype, result from alternative initiations of translation at three CUG and one AUG start codons. We showed here by Western immunoblotting and immunoprecipitation that the CUG-initiated forms of FGF-2 were synthesized in transformed cells, whereas "normal" cells almost exclusively produced the AUG-initiated form. CUG-initiated FGF-2 was induced in primary skin fibroblasts in response to heat shock and oxidative stress. In transformed cells and in stressed fibroblasts, CUG expression was dependent on cis-elements within the 5' region of FGF-2 mRNA and was not correlated to mRNA level, indicating a translational regulation. UV cross-linking experiments revealed that CUG expression was linked to the binding of several cellular proteins to FGF-2 mRNA 5' region. Since translation of FGF-2 mRNA was previously shown to occur by internal ribosome entry, a nonclassical mechanism already described for picornaviruses, the cross-linking patterns of FGF-2 and picornavirus mRNAs were compared. Comigration of several proteins, including a p60, was observed. However, this p60 was shown to be different from the p57/PTB internal entry factor, suggesting a specificity towards FGF-2 mRNA. We report here a process of translational activation of the FGF-2 CUG-initiated forms in direct relation with trans-acting factors specific to transformed and stressed cells. These data favor a critical role of CUG-initiated FGF-2 in cell transformation and in the stress response.
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17

Baldwin, Brenda R., Nikolai A. Timchenko, and Cynthia A. Zahnow. "Epidermal Growth Factor Receptor Stimulation Activates the RNA Binding Protein CUG-BP1 and Increases Expression of C/EBPβ-LIP in Mammary Epithelial Cells." Molecular and Cellular Biology 24, no. 9 (May 1, 2004): 3682–91. http://dx.doi.org/10.1128/mcb.24.9.3682-3691.2004.

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ABSTRACT The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is a key regulator of growth and differentiation in many tissues. C/EBPβ is expressed as several distinct protein isoforms (LAP1, LAP2, and LIP) whose expression is regulated by alternative translational initiation at downstream AUG start sites. The dominant-negative LIP isoform is predominantly expressed during proliferative cellular responses and is associated with aggressive tumors. In this study, we investigated a mechanism by which the LIP isoform is translationally regulated in mammary epithelial cells. We have demonstrated that LIP expression is increased in response to activation of the epidermal growth factor receptor (EGFR) signaling pathway and that the increased expression of LIP is regulated in part by an RNA binding protein referred to as CUG repeat binding protein (CUG-BP1). Our data demonstrate that EGFR signaling results in the phosphorylation of CUG-BP1 and this leads to an increase in the binding of CUG-BP1 to C/EBPβ mRNA and elevated expression of the LIP isoform. Phosphorylation is necessary for the binding activity of CUG-BP1 and the consequent increase in LIP expression, as determined by binding assays and a cell free, transcription-coupled translation system. CUG-BP1 is thus a previously unidentified downstream target of EGFR signaling and represents a new translational regulator of LIP expression in human mammary epithelial cells.
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18

Lorenzo, Armando J. "To V(CUG) or Not To V(CUG)—Can We Answer the Question?" Journal of Urology 187, no. 1 (January 2012): 11–12. http://dx.doi.org/10.1016/j.juro.2011.10.058.

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19

Botta, Sisir, and Hillary L. Copp. "To V(CUG) or Not to V(CUG) in Infants with Prenatal Hydronephrosis?" Journal of Urology 192, no. 3 (September 2014): 640–41. http://dx.doi.org/10.1016/j.juro.2014.06.062.

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20

Lim, Si Jie, Noor Dina Muhd Noor, Abu Bakar Salleh, and Siti Nurbaya Oslan. "Structure Prediction of a Thermostable SR74 α-Amylase from Geobacillus stearothermophilus Expressed in CTG-Clade Yeast Meyerozyma guilliermondii Strain SO." Catalysts 10, no. 9 (September 15, 2020): 1059. http://dx.doi.org/10.3390/catal10091059.

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α-amylase which catalyzes the hydrolysis of α-1,4-glycosidic bonds in starch have frequently been cloned into various microbial workhorses to yield a higher recombinant titer. A thermostable SR74 α-amylase from Geobacillus stearothermophilus was found to have a huge potential in detergent industries due to its thermostability properties. The gene was cloned into a CTG-clade yeast Meyerozyma guilliermondii strain SO. However, the CUG ambiguity present in the strain SO has possibly altered the amino acid residues in SR74 amylase wild type (WT) encoded by CUG the codon from the leucine to serine. From the multiple sequence alignment, six mutations were found in recombinant SR74 α-amylase (rc). Their effects on SR74 α-amylase structure and function remain unknown. Herein, we predicted the structures of the SR74 amylases (WT and rc) using the template 6ag0.1.A (PDB ID: 6ag0). We sought to decipher the possible effects of CUG ambiguity in strain SO via in silico analysis. They are structurally identical, and the metal triad (CaI–CaIII) might contribute to the thermostability while CaIV was attributed to substrate specificity. Since the pairwise root mean square deviation (RMSD) between the WT and rc SR74 α-amylase was lower than the template, we suggest that the biochemical properties of rc SR74 α-amylase were better deduced from its WT, especially its thermostability.
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Mykowska, Agnieszka, Krzysztof Sobczak, Marzena Wojciechowska, Piotr Kozlowski, and Wlodzimierz J. Krzyzosiak. "CAG repeats mimic CUG repeats in the misregulation of alternative splicing." Nucleic Acids Research 39, no. 20 (July 27, 2011): 8938–51. http://dx.doi.org/10.1093/nar/gkr608.

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22

Ladd, Andrea N., Nicolas Charlet-B., and Thomas A. Cooper. "The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing." Molecular and Cellular Biology 21, no. 4 (February 15, 2001): 1285–96. http://dx.doi.org/10.1128/mcb.21.4.1285-1296.2001.

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ABSTRACT Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. We previously described four muscle-specific splicing enhancers (MSEs) within introns flanking exon 5 in chicken cTNT that are both necessary and sufficient for exon inclusion in embryonic muscle. We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Here we report that CUG-BP is one of a novel family of developmentally regulated RNA binding proteins that includes embryonically lethal abnormal vision-type RNA binding protein 3 (ETR-3). This family, which we call CELF proteins for CUG-BP- and ETR-3-like factors, specifically bound MSE-containing RNAs in vitro and activated MSE-dependent exon inclusion of cTNT minigenes in vivo. The expression of two CELF proteins is highly restricted to brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed, and expression is developmentally regulated in striated muscle and brain. Changes in the level of expression and isoforms of ETR-3 in two different developmental systems correlated with regulated changes in cTNT splicing. A switch from cTNT exon skipping to inclusion tightly correlated with induction of ETR-3 protein expression during differentiation of C2C12 myoblasts. During heart development, the switch in cTNT splicing correlated with a transition in ETR-3 protein isoforms. We propose that ETR-3 is a major regulator of cTNT alternative splicing and that the CELF family plays an important regulatory role in cell-specific alternative splicing during normal development and disease.
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Matravadia, Sarthak, Vanessa B. Martino, Daniel Sinclair, David M. Mutch, and Graham P. Holloway. "Exercise training increases the expression and nuclear localization of mRNA destabilizing proteins in skeletal muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 7 (October 1, 2013): R822—R831. http://dx.doi.org/10.1152/ajpregu.00590.2012.

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While a paucity of information exists regarding posttranscriptional mechanisms influencing mitochondrial biogenesis, in resting muscle the stability of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA has been linked to mitochondrial content. Therefore, in the current study we have examined whether exercise promotes mRNA accumulation through the induction of proteins affiliated with mRNA stabilization (human antigen R, HuR) or conversely by decreasing the expression of mRNA destabilizing proteins [AU-rich binding factor (AUF1) and CUG binding protein (CUG-BP1)]. A single bout of exercise increased ( P < 0.05) the mRNA content of the transcriptional coactivator PGC-1α ∼3.5-fold without affecting mRNA content for HuR, CUG-BP1, or AUF1. One week of treadmill exercise training did not alter markers of mitochondrial content, the mRNA stabilizing protein HuR, or the mRNA destabilizing protein AUF1. In contrast, the mRNA destabilizing protein CUG-BP1 increased ∼40%. Four weeks of treadmill training increased the content of subunits of the electron transport chain ∼50%, suggesting induction of mitochondrial biogenesis. Expression levels for HuR and CUG-BP1 were not altered with chronic training; however, AUF1 expression was increased posttraining. Specifically, training increased ( P < 0.05) total muscle expression of two of four AUF1 isoforms ∼50% (AUF1p37, AUF1p40). Interestingly, these two isoforms were not detected in isolated nuclei; however, a large band representing the other two isoforms (AUF1p42, AUF1p45) was present in nuclei and increased ∼35% following chronic training. Altogether the current data provides evidence that mitochondrial biogenesis occurs in the presence of increased CUG-BP1 and AUF1, suggesting that reductions in known mRNA destabilizing proteins likely does not contribute to exercise-induced mitochondrial biogenesis.
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Lu, Xiaodan, Shengqing Hu, Yunfei Liao, Juan Zheng, Tianshu Zeng, Xueyu Zhong, Geng Liu, Luoning Gou, and Lulu Chen. "Vascular endothelial growth factor B promotes transendothelial fatty acid transport into skeletal muscle via histone modifications during catch-up growth." American Journal of Physiology-Endocrinology and Metabolism 319, no. 6 (December 1, 2020): E1031—E1043. http://dx.doi.org/10.1152/ajpendo.00090.2020.

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Caloric restriction (CR) followed by refeeding, a phenomenon known as catch-up growth (CUG), results in excessive lipid deposition and insulin resistance in skeletal muscle, but the underlying mechanisms remain elusive. Recent reports have suggested that vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation by regulating endothelial fatty acid transport. Here, we found continuous activation of VEGF-B signaling and increased lipid uptake in skeletal muscle from CR to refeeding, as well as increased lipid deposition and impaired insulin sensitivity after refeeding in the skeletal muscle of CUG rodents. Inhibiting VEGF-B signaling reduced fatty acid uptake in and transport across endothelial cells. Knockdown of Vegfb in the tibialis anterior (TA) muscle of CUG mice significantly attenuated muscle lipid accumulation and ameliorated muscle insulin sensitivity by decreasing lipid uptake. Furthermore, we showed that aberrant histone methylation (H3K9me1) and acetylation (H3K14ac and H3K18ac) at the Vegfb promoter might be the main cause of persistent VEGF-B upregulation in skeletal muscle during CUG. Modifying these aberrant loci using their related enzymes [PHD finger protein 2 (PHF2) or E1A binding protein p300 (p300)] could regulate VEGF-B expression in vitro. Collectively, our findings indicate that VEGF-B can promote transendothelial lipid transport and lead to lipid overaccumulation and insulin resistance in skeletal muscle during CUG, which might be mediated by histone methylation and acetylation.
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Pelletier, Richard, Maria M. Krasilnikova, George M. Samadashwily, Robert Lahue, and Sergei M. Mirkin. "Replication and Expansion of Trinucleotide Repeats in Yeast." Molecular and Cellular Biology 23, no. 4 (February 15, 2003): 1349–57. http://dx.doi.org/10.1128/mcb.23.4.1349-1357.2003.

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ABSTRACT The mechanisms of trinucleotide repeat expansions, underlying more than a dozen hereditary neurological disorders, are yet to be understood. Here we looked at the replication of (CGG) n · (CCG) n and (CAG) n · (CTG) n repeats and their propensity to expand in Saccharomyces cerevisiae. Using electrophoretic analysis of replication intermediates, we found that (CGG) n · (CCG) n repeats significantly attenuate replication fork progression. Replication inhibition for this sequence becomes evident at as few as ∼10 repeats and reaches a maximal level at 30 to 40 repeats. This is the first direct demonstration of replication attenuation by a triplet repeat in a eukaryotic system in vivo. For (CAG) n · (CTG) n repeats, on the contrary, there is only a marginal replication inhibition even at 80 repeats. The propensity of trinucleotide repeats to expand was evaluated in a parallel genetic study. In wild-type cells, expansions of (CGG)25 · (CCG)25 and (CAG)25 · (CTG)25 repeat tracts occurred with similar low rates. A mutation in the large subunit of the replicative replication factor C complex (rfc1-1) increased the expansion rate for the (CGG)25 repeat ∼50-fold but had a much smaller effect on the expansion of the (CTG)25 repeat. These data show dramatic sequence-specific expansion effects due to a mutation in the lagging strand DNA synthesis machinery. Together, the results of this study suggest that expansions are likely to result when the replication fork attempts to escape from the stall site.
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Khandelwal, P., V. Jain, A. K. Gupta, M. Kalaivani, and V. K. Paul. "Association of early postnatal growth trajectory with body composition in term low birth weight infants." Journal of Developmental Origins of Health and Disease 5, no. 3 (March 18, 2014): 189–96. http://dx.doi.org/10.1017/s2040174414000178.

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Growth acceleration or catch-up growth (CUG) in early infancy is a plausible risk factor for later obesity and cardiovascular disease. We postulate that this risk may be mediated by an adverse programming of body composition by CUG in early infancy. The study was aimed at evaluating the association between the pattern of gain in weight and length of term low birth weight (LBW) infants from birth to 6 months, with fat mass percent (FM%) at 6 months. Term healthy singleton LBW infants were enrolled. Baby’s weight and length z-scores were measured at birth and three follow-up visits. Body composition was measured by dual-energy absorptiometry at last visit. A total of 54 babies (28 boys) were enrolled. The mean birth weight and gestation were 2175±180 g and 37.6±0.6 weeks. Follow-up visits were at 1.4±0.0, 3.0±0.3 and 7.2±0.8 months. The proportion of babies who showed CUG [increase in weight for age z-score (∆WAZ)>0.67] from birth to 1.4, 3.0 and 7.2 months was 29.6, 26.4 and 48.5%, respectively. The mean FM% at 7.2 months was 16.6±7.8%. Infants with greater ∆WAZ from birth to 3 and 7.2 months had significantly greater FM% at 7.2 months after adjusting for current age, size and gender. Infants with early CUG (<1.4 months) had higher FM% than infants with no CUG. We conclude that earlier and greater increment in WAZ is positively associated with FM%.
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Sen, Supriya, Indrani Talukdar, and Nicholas J. G. Webster. "SRp20 and CUG-BP1 Modulate Insulin Receptor Exon 11 Alternative Splicing." Molecular and Cellular Biology 29, no. 3 (December 1, 2008): 871–80. http://dx.doi.org/10.1128/mcb.01709-08.

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ABSTRACT The insulin receptor (IR) exists as two isoforms, IR-A and IR-B, which result from alternative splicing of exon 11 in the primary transcript. This alternative splicing is cell specific, and the relative proportions of exon 11 isoforms also vary during development, aging, and different disease states. We have previously demonstrated that both intron 10 and exon 11 contain regulatory sequences that affect IR splicing both positively and negatively. In this study, we sought to define the precise sequence elements within exon 11 that control exon recognition and cellular factors that recognize these elements. Using minigenes carrying linker-scanning mutations within exon 11, we detected both exonic splicing enhancer and exonic splicing silencer elements. We identified binding of SRp20 and SF2/ASF to the exonic enhancers and CUG-BP1 to the exonic silencer by RNA affinity chromatography. Overexpression and knockdown studies with hepatoma and embryonic kidney cells demonstrated that SRp20 and SF2/ASF increase exon inclusion but that CUG-BP1 causes exon skipping. We found that CUG-BP1 also binds to an additional intronic splicing silencer, located at the 3′ end of intron 10, to promote exon 11 skipping. Thus, we propose that SRp20, SF2/ASF, and CUG-BP1 act antagonistically to regulate IR alternative splicing in vivo and that the relative ratios of SRp20 and SF2/ASF to CUG-BP1 in different cells determine the degree of exon inclusion.
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Herrendorff, Ruben, Maria Teresa Faleschini, Adeline Stiefvater, Beat Erne, Tatiana Wiktorowicz, Frances Kern, Matthias Hamburger, Olivier Potterat, Jochen Kinter, and Michael Sinnreich. "Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I." Journal of Biological Chemistry 291, no. 33 (June 13, 2016): 17165–77. http://dx.doi.org/10.1074/jbc.m115.710616.

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Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases.
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Starck, Shelley R., Vivian Jiang, Mariana Pavon-Eternod, Sharanya Prasad, Brian McCarthy, Tao Pan, and Nilabh Shastri. "Leucine-tRNA Initiates at CUG Start Codons for Protein Synthesis and Presentation by MHC Class I." Science 336, no. 6089 (June 28, 2012): 1719–23. http://dx.doi.org/10.1126/science.1220270.

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Effective immune surveillance by cytotoxic T cells requires newly synthesized polypeptides for presentation by major histocompatibility complex (MHC) class I molecules. These polypeptides are produced not only from conventional AUG-initiated, but also from cryptic non–AUG-initiated, reading frames by distinct translational mechanisms. Biochemical analysis of ribosomal initiation complexes at CUG versus AUG initiation codons revealed that cells use an elongator leucine-bound transfer RNA (Leu-tRNA) to initiate translation at cryptic CUG start codons. CUG/Leu-tRNA initiation was independent of the canonical initiator tRNA (AUG/Met-tRNAiMet) pathway but required expression of eukaryotic initiation factor 2A. Thus, a tRNA-based translation initiation mechanism allows non–AUG-initiated protein synthesis and supplies peptides for presentation by MHC class I molecules.
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30

Bugler, B., F. Amalric, and H. Prats. "Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor." Molecular and Cellular Biology 11, no. 1 (January 1991): 573–77. http://dx.doi.org/10.1128/mcb.11.1.573.

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Three forms of basic fibroblast growth factor (bFGF), initiated at an AUG (18 kDa) and two CUG (21 and 22.5 kDa) start codons, were produced following transfection of COS cells with human hepatoma bFGF cDNA. The subcellular localization of the different forms was investigated directly or by using chimeric genes constructed by fusion of the bFGF and chloramphenicol acetyltransferase open reading frames. The AUG-initiated proteins were cytoplasmic, while the CUG-initiated forms were nuclear. The signal sequence responsible for the nuclear localization of bFGF is contained within 37 amino acid residues between the second CUG and the AUG start codons. Alternative initiation of translation regulates the subcellular localization of bFGF and thus could modulate its role in cell growth and differentiation control.
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Bugler, B., F. Amalric, and H. Prats. "Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor." Molecular and Cellular Biology 11, no. 1 (January 1991): 573–77. http://dx.doi.org/10.1128/mcb.11.1.573-577.1991.

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Three forms of basic fibroblast growth factor (bFGF), initiated at an AUG (18 kDa) and two CUG (21 and 22.5 kDa) start codons, were produced following transfection of COS cells with human hepatoma bFGF cDNA. The subcellular localization of the different forms was investigated directly or by using chimeric genes constructed by fusion of the bFGF and chloramphenicol acetyltransferase open reading frames. The AUG-initiated proteins were cytoplasmic, while the CUG-initiated forms were nuclear. The signal sequence responsible for the nuclear localization of bFGF is contained within 37 amino acid residues between the second CUG and the AUG start codons. Alternative initiation of translation regulates the subcellular localization of bFGF and thus could modulate its role in cell growth and differentiation control.
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32

Kim, Ji Hyun, Dong Ho Kim, and Jung Sub Lim. "Growth status of children and adolescents born small for gestational age at full term in Korea: data from the KNHANES-V." Journal of Pediatric Endocrinology and Metabolism 33, no. 6 (May 24, 2020): 743–50. http://dx.doi.org/10.1515/jpem-2019-0471.

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AbstractObjectivesSmall for gestational age (SGA) status is known to show stunted growth and results in short stature in adults. The aim of this study was to describe the current short stature in subjects born SGA in Korea and to assess catch-up growth (CUG) or non-CUG.MethodsWe analyzed data from 3,524 subjects (1,831 male) aged 1–18 years who were born as full-term singletons and who participated in the Fifth Korean National Health and Nutrition Examination Survey (2010–2011).ResultsThe prevalence of SGA was 13.4% (n=471). Subjects born SGA had fathers with shorter height, shorter mother’s height, and mid-parental height than non-SGA subjects (p<0.05 for all). The odds ratios (ORs) for SGA birth of a short statured father and a short statured mother were 2.00 (95% CI; 1.15–3.47) and 2.11 (95% CI; 1.30–3.40), respectively. Among 471 SGA subjects, 28 subjects (5.9%) were non-CUG, which made up 36.4% of all subjects with short stature. The CUG subjects had a higher father's height, mother’s height, mid-parental height, and current BMI (p<0.05 for all). The non-CUG subjects had a higher percentage of fathers being near-short stature (height<10th percentile; 33.3 vs. 12.7%; p=0.008) and mothers being near-short stature (39.3 vs. 13.9%; p<0.001).ConclusionKorean subjects born SGA had a higher risk of current short stature. This population-based nationwide survey also showed that both father’s and mother’s short stature are risk factors of not only SGA birth but also non-CUG in their children.
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Pinheiro, Philip, Garry Scarlett, Alison Rodger, P. Mark Rodger, Anna Murray, Tom Brown, Sarah F. Newbury, and James A. McClellan. "Structures of CUG Repeats in RNA." Journal of Biological Chemistry 277, no. 38 (June 19, 2002): 35183–90. http://dx.doi.org/10.1074/jbc.m202235200.

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34

Souza, Lucéia Fátima, Niara da Silva Medeiros, Paula Cilene Pereira dos Santos, Carlos Henrique Pagno, Cleice Dalla Nora, Erna Vogt de Jong, and Alessandro de Oliveira Rios. "Antioxidants from Annatto Seeds as Possible Inhibitory Agents of the Hepatotoxicity Induced by the Antitumor Agent Cisplatin." Natural Product Communications 11, no. 9 (September 2016): 1934578X1601100. http://dx.doi.org/10.1177/1934578x1601100909.

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The effects of annatto seeds and of bixin on the oxidative damage induced by cisplatin in male Wistar rats was evaluated in the present study by way of lipid peroxidation, weight gain, the food efficiency coefficient, fat deposits in the hepatocytes and dosing of the enzymes in this organ. The animals were divided into four groups: control group (CG), cisplatin group (CPG), bixin+cisplatin group (CBG) and annatto+cisplatin group (CUG). Cisplatin (5 mg/kg body weight) was injected intraperitoneally 48 hours before the end of the experiment. The bixin and annatto were administered daily together with the commercial feed. The pre-treatment with annatto and bixin attenuated the cisplatin-induced liver damage and significantly reduced the enzymes AST and ALT. Annatto was shown to be capable of inhibiting lipid peroxidation as determined by TBARS. These results suggest that annatto seeds and bixin could be important agents in the reduction of cisplatin-induced hepatotoxicity.
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35

Raaijmakers, Renée H. L., Lise Ripken, C. Rosanne M. Ausems, and Derick G. Wansink. "CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities." International Journal of Molecular Sciences 20, no. 15 (July 27, 2019): 3689. http://dx.doi.org/10.3390/ijms20153689.

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CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the DMPK/DM1-AS gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in DMPK. Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients.
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Priest, Shelby J., and Michael C. Lorenz. "Characterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade." Eukaryotic Cell 14, no. 9 (July 6, 2015): 931–40. http://dx.doi.org/10.1128/ec.00062-15.

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ABSTRACTCandidaspecies cause a variety of mucosal and invasive infections and are, collectively, the most important human fungal pathogens in the developed world. The majority of these infections result from a few related species within the “CUG clade,” so named because they use a nonstandard translation for that codon. Some members of the CUG clade, such asCandida albicans, present significant clinical problems, whereas others, such asCandida(Meyerozyma)guilliermondii, are uncommon in patients. The differences in incidence rates are imperfectly correlated with virulence in animal models of infection, but comparative analyses that might provide an explanation for why some species are effective pathogens and others are not have been rare or incomplete. To better understand the phenotypic basis for these differences, we characterized eight CUG clade species—C. albicans,C. dubliniensis,C. tropicalis,C. parapsilosis,Clavispora lusitaniae,M. guilliermondii,Debaryomyces hansenii, andLodderomyces elongisporus—for host-relevant phenotypes, including nutrient utilization, stress tolerance, morphogenesis, interactions with phagocytes, and biofilm formation. Two species deviated from expectations based on animal studies and human incidence.C. dubliniensiswas quite robust, grouping in nearly all assays with the most virulent species,C. albicansandC. tropicalis, whereasC. parapsilosiswas substantially less fit than might be expected from its clinical importance. These findings confirm the utility ofin vitromeasures of virulence and provide insight into the evolution of virulence in the CUG clade.
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Jones, Karlie, Christina Wei, Benedikt Schoser, Giovanni Meola, Nikolai Timchenko, and Lubov Timchenko. "Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5." Proceedings of the National Academy of Sciences 112, no. 26 (June 15, 2015): 8041–45. http://dx.doi.org/10.1073/pnas.1422273112.

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Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DM is caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2.
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Timchenko, Lubov. "Correction of RNA-Binding Protein CUGBP1 and GSK3β Signaling as Therapeutic Approach for Congenital and Adult Myotonic Dystrophy Type 1." International Journal of Molecular Sciences 21, no. 1 (December 21, 2019): 94. http://dx.doi.org/10.3390/ijms21010094.

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Myotonic dystrophy type 1 (DM1) is a complex genetic disease affecting many tissues. DM1 is caused by an expansion of CTG repeats in the 3′-UTR of the DMPK gene. The mechanistic studies of DM1 suggested that DMPK mRNA, containing expanded CUG repeats, is a major therapeutic target in DM1. Therefore, the removal of the toxic RNA became a primary focus of the therapeutic development in DM1 during the last decade. However, a cure for this devastating disease has not been found. Whereas the degradation of toxic RNA remains a preferential approach for the reduction of DM1 pathology, other approaches targeting early toxic events downstream of the mutant RNA could be also considered. In this review, we discuss the beneficial role of the restoring of the RNA-binding protein, CUGBP1/CELF1, in the correction of DM1 pathology. It has been recently found that the normalization of CUGBP1 activity with the inhibitors of GSK3 has a positive effect on the reduction of skeletal muscle and CNS pathologies in DM1 mouse models. Surprisingly, the inhibitor of GSK3, tideglusib also reduced the toxic CUG-containing RNA. Thus, the development of the therapeutics, based on the correction of the GSK3β-CUGBP1 pathway, is a promising option for this complex disease.
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Kress, Chantal, Carole Gautier-Courteille, H. Beverley Osborne, Charles Babinet, and Luc Paillard. "Inactivation of CUG-BP1/CELF1 Causes Growth, Viability, and Spermatogenesis Defects in Mice." Molecular and Cellular Biology 27, no. 3 (November 27, 2006): 1146–57. http://dx.doi.org/10.1128/mcb.01009-06.

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ABSTRACT CUG-BP1/CELF1 is a multifunctional RNA-binding protein involved in the regulation of alternative splicing and translation. To elucidate its role in mammalian development, we produced mice in which the Cugbp1 gene was inactivated by homologous recombination. These Cugbp1 − / − mice were viable, although a significant portion of them did not survive after the first few days of life. They displayed growth retardation, and most Cugbp1 − / − males and females exhibited impaired fertility. Male infertility was more thoroughly investigated. Histological examination of testes from Cugbp1 − / − males showed an arrest of spermatogenesis that occurred at step 7 of spermiogenesis, before spermatid elongation begins, and an increased apoptosis. A quantitative reverse transcriptase PCR analysis showed a decrease of all the germ cell markers tested but not of Sertoli and Leydig markers, suggesting a general decrease in germ cell number. In wild-type testes, CUG-BP1 is expressed in germ cells from spermatogonia to round spermatids and also in Sertoli and Leydig cells. These findings demonstrate that CUG-BP1 is required for completion of spermatogenesis.
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Li, Jinxing, Jun Matsumoto, Li-Ping Bai, Asako Murata, Chikara Dohno, and Kazuhiko Nakatani. "A Ligand That Targets CUG Trinucleotide Repeats." Chemistry - A European Journal 22, no. 42 (August 30, 2016): 14881–89. http://dx.doi.org/10.1002/chem.201602741.

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Li, Jinxing, Jun Matsumoto, Li-Ping Bai, Asako Murata, Chikara Dohno, and Kazuhiko Nakatani. "A Ligand That Targets CUG Trinucleotide Repeats." Chemistry - A European Journal 22, no. 42 (August 25, 2016): 14761. http://dx.doi.org/10.1002/chem.201603857.

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42

Belkozhayev A.M. and Niyazova R.Ye. "THE INTERACTION OF miR-4258, miR-3960, miR-211-3p AND miR-3155b WITH mRNAs GENES OF NON-POLYGLUTAMINE TRINUCLEOTIDE DISORDERS." SERIES OF BIOLOGICAL AND MEDICAL 1, no. 337 (February 15, 2020): 25–32. http://dx.doi.org/10.32014/2020.2519-1629.4.

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Trinucleotide repeat expansion disorders constitute a group of dominantly inherited neurological diseases that are incurable and ultimately fatal. In the present work, miRNA binding sites were predicted by the MirTarget program. It was given characteristics of miRNAs binding sites in 5' and 3' UTR mRNAs genes of non-polyglutamine trinucleotide disorders with CGG, GCC, CUG repeats. Binding sites of 2567 miRNAs with mRNAs of 17494 human genes were determined. 206 genes with nucleotide repeats, mRNAs of which are bind with miRNA in the 5'UTR and 3'UTR, were observed. From thus, 2668 miRNAs binding sites are located in the 5'UTR, 3853 – in the 3'UTR with ΔG/ΔGm values equal to 85 % and more. It was found that 34 gene’s mRNA having trinucleotide (CGG\GCC\CUG) repeats were targets for miR-4258, miR-3960 miR-211-3p and miR-3155b. miR-4258 binds to mRNA of ADARB1, C11orf87 and CBFB genes with free binding energy - 93 kJ/mole and ΔG/ΔGm 91%, to mRNA of ARHGEF7, BCR, BRSK2 and C9orf91 genes with free binding energy - 91 kJ/mole and ΔG/ΔGm 89%. miR-3960 binds in GCC repeats to mRNA of ABCC1 and BLMH genes with free binding energy - 116 kJ/mole. miR-211-3p and miR-3155b interact with mRNA of ACACA and ANKRD13D genes in 5’-3’untranslated regions. Studying binding characteristics of miRNA and genes will help identify association of miRNAs with genes with trinucleotide repeats for recommending for the diagnosis of nucleotide repeat expansion disorders.
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Grande, Valentina, Denisa Hathazi, Emily O’Connor, Theo Marteau, Ulrike Schara-Schmidt, Andreas Hentschel, Genevieve Gourdon, Nikoletta Nikolenko, Hanns Lochmüller, and Andreas Roos. "Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 603–19. http://dx.doi.org/10.3233/jnd-200558.

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Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3′-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3β), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3β-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3βby unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80– 150) and high (2600– 3600) CTG-repeats. Apart from GSK3β increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3β. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3β inhibitor treatment responses.
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Masarwi, Majdi, Raanan Shamir, Moshe Phillip, and Galia Gat-Yablonski. "Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency." Journal of Endocrinology 237, no. 3 (June 2018): 229–42. http://dx.doi.org/10.1530/joe-18-0028.

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Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90–120 days of re-feeding. In vitro studies were performed on ATDC5 cells. Analyses of mRNA and protein levels were done using qPCR and Western blot, respectively. CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re-feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children.
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45

Wang, Li-Chun, Kuan-Yu Chen, Huichin Pan, Chia-Chieh Wu, Po-Hsuan Chen, Yuan-Ting Liao, Chin Li, Min-Lang Huang, and Kuang-Ming Hsiao. "Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans." Cellular and Molecular Life Sciences 68, no. 7 (September 17, 2010): 1255–67. http://dx.doi.org/10.1007/s00018-010-0522-4.

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46

Ribelles, Alfredo, Carmen Galbis-Estrada, Maria A. Parras, Bárbara Vivar-Llopis, Carla Marco-Ramírez, and Manuel Diaz-Llopis. "Ocular Surface and Tear Film Changes in Older Women Working with Computers." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/467039.

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The aim of this work is to investigate changes in the ocular surface (OS) and tear film (TF) by means of questionnaire-based subjective symptoms, TF break-up time, Schirmer test, and TF analysis in women working with computers and to analyze the effects of the oral supplementation with antioxidants/omega 3 fatty acids (A/ω3) in the OS outcomes. Women aged 40–65 years (n=148) were recruited at the Administrative Offices of Valencia (Spain) and distributed into two age groups, 40–52 years (AGE1;n=87) and 53–65 years (AGE2;n=61), and then subdivided according to being (or not) computer users (CUG; NCUG) during the workday. Homogeneous subgroups were randomly assigned (or not) to the daily intake of three pills of A/ω3 for three months. At baseline and at the end of follow-up, personalized interviews and ocular examination were done. Reflex tear samples were collected from the inferior meniscus and processed for a multiplexed particle-based flow cytometry assay to measure proinflammatory molecules. Statistics were performed using the SPSS 15.0 program. The OS pathology was clinically evident in the AGE1-CUG (33%) versus the AGE2-CUG (64%) of women. Significantly higher interleukins-1βand -6 tear levels were found in the AGE1 versus the AGE2 women employees (P=0.006andP=0.001, resp.), as well as in the CUG versus the NCUG (P=0.001andP=0.000, resp.). Supplementation with A/ω3 positively influenced the OS pathology as manifested by the amelioration of the clinical signs/symptoms related to computer uses. Strategies involving a safe environment and oral micronutrient supplements may be managed within eye-care standards in older women.
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47

Hagler, Lauren D., Sarah E. Bonson, Philip A. Kocheril, and Steven C. Zimmerman. "Assessing the feasibility and stability of uracil base flipping in RNA–small molecule complexes using molecular dynamics simulations." Canadian Journal of Chemistry 98, no. 6 (June 2020): 261–69. http://dx.doi.org/10.1139/cjc-2019-0421.

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Small molecules can be used to target RNAs that mediate disease. A fundamental understanding of binding interactions between RNA and small molecules and the structure of their complexes will further inform the design of new targeting agents. Two small molecule ligands were investigated for their ability to recognize the expanded CUG repeat sequence in RNA, the causative agent of myotonic dystrophy type 1. We report the use of molecular dynamics simulations to explore small molecule–RNA complexes and the finding of a stabilized base flipped conformation at UU mismatches. The results of this computational study support experimental observations and suggest that base flipping is feasible for CUG-repeat RNA.
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48

Tusi, Solaleh Khoramian, Lien Nguyen, Kiruphagaran Thangaraju, Jian Li, John D. Cleary, Tao Zu, and Laura P. W. Ranum. "The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG•CAGG repeats." Human Molecular Genetics 30, no. 11 (April 15, 2021): 1020–29. http://dx.doi.org/10.1093/hmg/ddab098.

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Abstract Repeat-associated non-ATG (RAN) proteins have been reported in 11 microsatellite expansion disorders but the factors that allow RAN translation to occur and the effects of different repeat motifs and alternative AUG-like initiation codons are unclear. We studied the mechanisms of RAN translation across myotonic dystrophy type 2 (DM2) expansion transcripts with (CCUG) or without (CAGG) efficient alternative AUG-like codons. To better understand how DM2 LPAC and QAGR RAN proteins are expressed, we generated a series of CRISPR/Cas9-edited HEK293T cell lines. We show that LPAC and QAGR RAN protein levels are reduced in protein kinase R (PKR)−/− and PKR-like endoplasmic reticulum kinase (PERK)−/− cells, with more substantial reductions of CAGG-encoded QAGR in PKR−/− cells. Experiments using mutant eIF2α-S51A HEK293T cells show that p-eIF2α is required for QAGR production. In contrast, LPAC levels were only partially reduced in these cells, suggesting that both non-AUG and close-cognate initiation occur across CCUG RNAs. Overexpression of the alternative initiation factor eIF2A increases LPAC and QAGR protein levels but, notably, has a much larger effect on QAGR expressed from CAGG-expansion RNAs that lack efficient close-cognate codons. The effects of eIF2A on increasing LPAC are consistent with previous reports that eIF2A affects CUG-initiation translation. The observation that eIF2A also increases QAGR proteins is novel because CAGG expansion transcripts do not contain CUG or similarly efficient close-cognate AUG-like codons. For QAGR but not LPAC, the eIF2A-dependent increases are not seen when p-eIF2α is blocked. These data highlight the differential regulation of DM2 RAN proteins and eIF2A as a potential therapeutic target for DM2 and other RAN diseases.
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49

Galka-Marciniak, Paulina, Martyna O. Urbanek, and Wlodzimierz J. Krzyzosiak. "Triplet repeats in transcripts: structural insights into RNA toxicity." Biological Chemistry 393, no. 11 (November 1, 2012): 1299–315. http://dx.doi.org/10.1515/hsz-2012-0218.

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Abstract Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington’s disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.
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50

Loughran, Gary, Alexander V. Zhdanov, Maria S. Mikhaylova, Fedor N. Rozov, Petr N. Datskevich, Sergey I. Kovalchuk, Marina V. Serebryakova, et al. "Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF." Proceedings of the National Academy of Sciences 117, no. 40 (September 21, 2020): 24936–46. http://dx.doi.org/10.1073/pnas.2001433117.

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While near-cognate codons are frequently used for translation initiation in eukaryotes, their efficiencies are usually low (<10% compared to an AUG in optimal context). Here, we describe a rare case of highly efficient near-cognate initiation. A CUG triplet located in the 5′ leader of POLG messenger RNA (mRNA) initiates almost as efficiently (∼60 to 70%) as an AUG in optimal context. This CUG directs translation of a conserved 260-triplet-long overlapping open reading frame (ORF), which we call POLGARF (POLG Alternative Reading Frame). Translation of a short upstream ORF 5′ of this CUG governs the ratio between POLG (the catalytic subunit of mitochondrial DNA polymerase) and POLGARF synthesized from a single POLG mRNA. Functional investigation of POLGARF suggests a role in extracellular signaling. While unprocessed POLGARF localizes to the nucleoli together with its interacting partner C1QBP, serum stimulation results in rapid cleavage and secretion of a POLGARF C-terminal fragment. Phylogenetic analysis shows that POLGARF evolved ∼160 million y ago due to a mammalian-wide interspersed repeat (MIR) transposition into the 5′ leader sequence of the mammalian POLG gene, which became fixed in placental mammals. This discovery of POLGARF unveils a previously undescribed mechanism of de novo protein-coding gene evolution.
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