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Journal articles on the topic "RTEL1"
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Landry, Aaron P., and Huangen Ding. "The N-Terminal Domain of Human DNA Helicase Rtel1 Contains a Redox Active Iron-Sulfur Cluster." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/285791.
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Human telomere length regulator Rtel1 is a superfamily II DNA helicase and is essential for maintaining proper length of telomeres in chromosomes. Here we report that the N-terminal domain of human Rtel1 (RtelN) expressed inEscherichia colicells produces a protein that contains a redox active iron-sulfur cluster with the redox midpoint potential of −248 ± 10 mV (pH 8.0). The iron-sulfur cluster in RtelN is sensitive to hydrogen peroxide and nitric oxide, indicating that reactive oxygen/nitrogen species may modulate the DNA helicase activity of Rtel1 via modification of its iron-sulfur cluster. Purified RtelN retains a weak binding affinity for the single-stranded (ss) and double-stranded (ds) DNAin vitro. However, modification of the iron-sulfur cluster by hydrogen peroxide or nitric oxide does not significantly affect the DNA binding activity of RtelN, suggesting that the iron-sulfur cluster is not directly involved in the DNA interaction in the N-terminal domain of Rtel1.
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Gutierrez-Rodrigues, Fernanda, Sachiko Kajigaya, Xingmin Feng, Maria del Pilar Fernandez Ibanez, Marie J. Desierto, Keyvan Keyvanfar, Zejuan Li, et al. "Heterozygous RTEL1 variants in Patients with Bone Marrow Failure Associate with Telomere Dysfunction in the Absence of Telomere Shortening." Blood 128, no. 22 (December 2, 2016): 1044. http://dx.doi.org/10.1182/blood.v128.22.1044.1044.
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Abstract The pathophysiology of bone marrow failure (BMF) can be immune, as in acquired aplastic anemia (AA), or constitutional, due to germline mutations in genes critical for DNA repair and telomere maintenance. Variability in penetrance and phenotype can complicate diagnosis, as patients with underlying genetic defects may present in adulthood and without characteristic physical anomalies. RTEL1 encodes a helicase crucial for telomere maintenance and DNA repair. The gene has two main transcripts in human cells: the 1300 amino acid isoform 3 and the 1219 amino acid isoform 1. RTEL1 isoform 3 contains a conserved C4C4-RING domain responsible for resolving the t-loop required for telomere replication. Using next-generation sequencing (NGS), RTEL1 germline variants with unknown clinical significance have been found in AA patients. Functional tests may elucidate RTEL1 variants' pathogenic role in telomere biology. Here, we describe RTEL1 heterozygous germline mutations in patients with BMF and investigate their impact in telomere maintenance. We screened 63 patients with a suggestive familial phenotype for germline mutations in peripheral blood cells using a targeted, 49 gene NGS panel. To investigate variants' impact in telomere functions, telomere length (TL) was measured by Southern blot (SB), t-circles were quantified by telomere circle assay, and single-stranded overhang was measured by non-denaturing SB. Eight patients carried novel heterozygous non-synonymous RTEL1 variants: four nucleotide changes were located in the RAD3 domain, six in the harmonin-like domain, and one in the RING domain. Clinical features and TL were heterogeneous (Table 1). The only RTEL1 variant predicted as pathogenic in silico was F1262L (c.3786 C>G) in patient 2; this mutation affects a highly conserved amino acid residue located in the RING domain, which is responsible for RTEL1 interaction with TRF2 at telomeres and t-loop unwinding. Patient 2 had very short telomeres, abnormal accumulation of t-circles, and eroded single-stranded telomeric overhangs in leukocytes, indicating a disrupted RTEL1 RING domain. To confirm observations made in clinical samples, 293T cells transfected with a plasmid carrying wild-type RTEL1-FLAG isoform 3 or its F1262L mutated version were assessed for TRF2 and FLAG co-localization in the nucleus. By confocal microscopy, wild-type RTEL1, but not mutant RTEL1 co-localized with TRF2. These findings strongly implicate RTEL1-F1262L as pathogenic, and thus the first autosomal dominant mutation in the RING domain in an AA patient. In patient 1, D743N variant in silico prediction was indeterminate, but telomeres were very short and there was a family history of typical telomeropathy (AA, liver cirrhosis, and pulmonary fibrosis) without any other suspicious germline mutations. The D743N variant is located close to the V745M variant that has been reported in a patient with dyskeratosis congenita. Increased amounts of t-circles and telomeric overhang attrition were observed in three other patients (#4, 5, and 7). While not specific for RTEL1 function, these results suggest telomere dysfunction, despite TLs in the normal range for patient 4 and 5. The RTEL1 P82L variant also appeared related to clonal evolution and leukemic progression observed in patient 5. For patients 3, 4, 6, 7, and 8, several mutations were observed in other genes concomitant to RTEL1, and a more complex genomic architecture may be the cause of patients' phenotype. A previously reported TERC variant, and a TERT variant of undetermined in silico prediction, could be pathogenic in patients 7 and 6, respectively. In these cases, RTEL1 variants may modulate disease, or represent only coincidental abnormalities. To our knowledge, this is the first report of heterozygous RTEL1 mutations in AA. We also describe a TL-independent association between RTEL1 haploinsufficiency and telomere dysfunction in humans. Haploinsufficiency of RTEL1 may disrupt DNA repair, destabilize the genome, and promote leukemogenesis by a mechanism different than typical accelerated telomere attrition associated with very short telomeres. T-circle quantification and overhang measurement may be better measures of telomere dysfunction in patients with RTEL1 variants than simple TL assessment. The combination of different functional tests was useful to the assessment of novel variants impact in telomere maintenance and DNA repair. Disclosures Fernandez Ibanez: GSK/Novartis: Research Funding. Desierto:GSK/Novartis: Research Funding. Townsley:GSK/Novartis: Research Funding. Young:GSK/Novartis: Research Funding.
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Schertzer, Michael, Laurent Jullien, André L. Pinto, Rodrigo T. Calado, Patrick Revy, and Arturo Londoño-Vallejo. "Human RTEL1 Interacts with KPNB1 (Importin β) and NUP153 and Connects Nuclear Import to Nuclear Envelope Stability in S-Phase." Cells 12, no. 24 (December 8, 2023): 2798. http://dx.doi.org/10.3390/cells12242798.
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Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in direct connection to origin firing. We discovered that inhibiting protein import also leads to similar, albeit non-cell cycle-related, nuclear envelope disruptions. Remarkably, overexpression of wild-type RTEL1, or of its C-terminal part lacking the helicase domain, protects cells against nuclear envelope anomalies mediated by protein import inhibition. We identified distinct domains in the C-terminus of RTEL1 essential for the interaction with KPNB1 (importin β) and NUP153, respectively, and we demonstrated that, on its own, the latter domain can promote the dynamic nuclear internalization of peptides that freely diffuse through the nuclear pore. Consistent with putative functions exerted in protein import, RTEL1 can be visualized on both sides of the nuclear pore using high-resolution microscopy. In all, our work points to an unanticipated, helicase-independent, role of RTEL1 in connecting both nucleocytoplasmic trafficking and nuclear envelope integrity to genome replication initiation in S-phase.
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Borie, Raphael, Diane Bouvry, Vincent Cottin, Clement Gauvain, Aurélie Cazes, Marie-Pierre Debray, Jacques Cadranel, et al. "Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes." European Respiratory Journal 53, no. 2 (February 2019): 1800508. http://dx.doi.org/10.1183/13993003.00508-2018.
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Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.
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Marsh, Judith C. W., Fernanda Gutierrez-Rodrigues, James Cooper, Jie Jiang, Shreyans Gandhi, Sachiko Kajigaya, Xingmin Feng, et al. "Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms." Blood Advances 2, no. 1 (January 4, 2018): 36–48. http://dx.doi.org/10.1182/bloodadvances.2017008110.
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Key Points RTEL1 variants associate with AA, idiopathic cytopenias, and hypocellular myelodysplastic syndromes. Detailed clinical/family history, functional assays, and in silico tools are critical for interpreting the pathogenicity of RTEL1 variants.
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Kannengiesser, Caroline, Raphael Borie, Christelle Ménard, Marion Réocreux, Patrick Nitschké, Steven Gazal, Hervé Mal, et al. "HeterozygousRTEL1mutations are associated with familial pulmonary fibrosis." European Respiratory Journal 46, no. 2 (May 28, 2015): 474–85. http://dx.doi.org/10.1183/09031936.00040115.
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Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genesTERT(reverse transcriptase) andTERC(RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF withoutTERTandTERCmutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygousRTEL1mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this,RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygousRTEL1mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus,RTEL1enlarges the number of telomere-associated genes implicated in FPF.
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Ballew, Bari J., Kevin B. Jacobs, Meredith Yeager, Neelam Giri, Joseph F. Boland, Belynda D. Hicks, Laurie Burdett, Amy A. Hutchinson, Blanche P. Alter, and Sharon A. Savage. "Germline Mutations in RTEL1 cause Dyskeratosis Congenita." Blood 120, no. 21 (November 16, 2012): 515. http://dx.doi.org/10.1182/blood.v120.21.515.515.
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Abstract Abstract 515 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that results from impaired telomere maintenance. The classic triad (dysplastic nails, skin pigmentation, and oral leukoplakia) is diagnostic of DC but significant clinical heterogeneity can exist, even within a family. Leukocyte telomere lengths less than the first percentile for age are diagnostic of DC. Patients with DC are at high risk of bone marrow failure (BMF), myelodysplastic syndrome, cancer, pulmonary fibrosis, liver disease and other complications. Currently, germline mutations in 1 of 8 telomere biology genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, and CTC1) are known to cause ∼50–60% of DC cases. Our longitudinal cohort study conducts detailed medical record review and clinical examinations of patients with DC and their family members. DC is diagnosed based on the presence of the diagnostic triad or 1 of the triad plus BMF. All DC patients had telomeres <1st percentile. Patients are classified as DC-like if they have telomeres <1st percentile and other features, such as BMF or family history, suggestive of DC. All participants in this study were negative for mutations in the known DC genes. We performed whole exome sequencing (WES) on two DC families using an enriched multiplexed sequencing library (Nimblegen v2) and sequenced on an Illumina HiSeq™. Variants were removed from analyses if they did not pass quality control filters or were present more than 3 times in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP). Since DC can be inherited in autosomal dominant, autosomal recessive, and X-linked manners, we evaluated all inheritance models in our families. Additionally, if healthy family members had very short telomeres, they were also evaluated as potential silent carriers, since this approach has facilitated the identification of other DC genes. Nonsynonymous variants were considered deleterious if SIFT, PolyPhen 2, and Condel predictions were consistent. Family 1 has 2 siblings with the Hoyeraal Hreidarsson syndrome (HH) variant of DC, which includes features of DC plus cerebellar hypoplasia. In that family, WES revealed autosomal dominant inheritance of a nonsense mutation in RTEL1 (Regulator of Telomere Elongation Helicase 1), p.Arg1010Stop. Their mother, who has lymphocyte telomere lengths at the 1st percentile, is a clinically silent carrier of this mutation; the severe phenotypes present in her children are likely an example of genetic anticipation. In family 2, we found 2 RTEL1 mutations, a nonsense (p.Arg998Stop) and a deleterious missense (p.Glu615Asp) mutation, that were inherited from the father and mother, respectively. One clinically healthy child inherited only the missense mutation, but has telomeres <1st percentile. The other child has HH and extremely short telomeres; he is a compound heterozygote, having inherited both the missense and nonsense mutations in RTEL1. We subsequently performed targeted sequencing of the entire RTEL1 gene in all of our mutation-negative DC (n=11) and DC-like (n=14) families. We identified missense mutations in RTEL1 in 2 additional families. Family 3 has 2 DC-like siblings, but only the proband's DNA was available for sequencing. He was heterozygous for a deleterious missense mutation (p.Ala645Thr) in a conserved helicase domain of RTEL1. In family 4, a mutation was inherited in an autosomal recessive manner by a proband with HH. This mutation is intronic except for a read-through transcript of RTEL1-TNFRSF6B, which utilizes an alternative exon 34. If translated, this variant results in the amino acid change p.Arg1264His, which is likely deleterious; if not, this mutation may affect nonsense-mediated decay or induce a regulatory change in RTEL1 expression. RTEL1 is an essential, evolutionarily conserved DNA helicase that is important for DNA replication and telomere elongation. Depletion of mRTEL1 from mouse embryonic stem cells results in telomeric loss and chromosomal instability. All individuals with germline RTEL1 mutations in this study have short telomeres, which underscores the functional importance of RTEL1 in human telomere maintenance. In summary, by employing WES followed by targeted sequencing, we discovered mutations in RTEL1 in 4 DC families, indicating that dysfunctional RTEL1 is a biologically plausible cause of DC. Disclosures: No relevant conflicts of interest to declare.
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Gandhi, Shreyans, Jie Jiang, Mariam Ibanez, Isabelle Callebaut, Judith CW Marsh, and Ghulam J. Mufti. "Heterozygous RTEL1 Variants Are Associated with Bone Marrow Failure and Abnormal Clinical Phenotype." Blood 128, no. 22 (December 2, 2016): 1043. http://dx.doi.org/10.1182/blood.v128.22.1043.1043.
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Abstract Introduction Heterozygous RTEL1 mutations have recently been described in familial pulmonary fibrosis (PF) but are not known to be associated with cytopenias or bone marrow failure (BMF), in contrast to heterozygous mutations in other telomere maintenance genes TERT, TERC and TINF2. Constitutional BMF syndromes typically present with less severe pancytopenia and it is often unclear if they have hypocellular MDS (hypoMDS) or non-severe AA (NSAA) morphologically. Methods We screened 284 patients with idiopathic AA or uncharacterised BMF and 172 patients with MDS or acute myeloid leukemia (AML) for TL and RTEL1 variants, and for the other currently known telomere gene complex (TGC) mutations, after excluding patients with Fanconi anemia, DBA or other known inherited BMF syndrome. TL was measured using a monochrome multiplex quantitative PCR method on peripheral blood mononuclear cells. Illumina Nextera-amplicon sequencing was used to screen exons of the DC genes (DKC1, TERC, TERT, RTEL1, CTC1, NHP10, NOP2, USB1, WRAP53, TINF2, PARN and ACD) by MiSeq platform. Constitutional DNA was also analysed in 10 patients (skin 9, buccal swab 1) with RTEL1 variants. A targeted gene panel of 24 genes of an Illumina Tru-Seq Custom Amplicon workflow and platform was used to identify genes frequently mutated in MDS/AML. Impact of mutations was predicted based on 3D structure information from comparative modelling for the helicase domain, comprising the HD1 and HD2 subdomains, a Fe-S cluster and an ARCH domain, and for two harmonin-like (HML) domains and a RING finger domain, located in the C-terminal regulatory region of RTEL1. Results Heterozygous RTEL1 variants were identified in 20 (4.4%) patients. RTEL1 variant allele frequency (VAF) was 45-70% consistent with heterozygous inheritance in all cases. TL was short in 18 (90%) patients, being < 1st centile in 15 and <10th centile in 3. 2 patients had normal TL, <20th centile and >50th centile, respectively. Median age was 35 years (range 18-73). 15/20 (75%) had a hypocellular BM (7 hypoMDS, 5 non-severe AA, 3 ICUS), and 1 each with RAEB1, RAEB2, CMML1, AML and isolated macrocytosis. 3 patients had abnormal karyotype: +8 (hypoMDS), -Y,+1,del(1) (hypoMDS), del7q (RAEB1). 2 other patients with hypoMDS had somatic mutations: U2AF1 (30% VAF) with ASXL1 (27% VAF); U2AF1 (43% VAF). Lung abnormalities were early PF (1), interstitial lung disease (1), and abnormal lung function with reduced TLCO (1) and an obstructive picture (1). Liver fibrosis with portal hypertension and varices and reticulate skin pigmentation were present in the patient with ILD, 2 patients had dystrophic nails, and 1 unexplained mild hepato-splenomegaly. 2 patients had familial MDS, 5 had a family history of cancers affecting first-degree relatives, and 2 had skeletal and cartilage anomalies, associated with learning difficulties in 1 patient. 8/15 patients with hypocellular BM required no treatment (5 hypoMDS and 3 NSAA), one hypoMDS had CR with ciclosporin and another underwent successful unrelated donor stem cell transplant; for NSAA, 2 received ATG with CSA, with PR followed by relapse in one, the other was lost to follow up, and 1 was androgen responsive. 16/20 (80%) patients are alive; 3 patients with RAEB or AML died of progressive disease and 1 patient with ICUS and severe constitutional features died from lymphoma 10 years after presentation. Mutations were spread throughout the entire RTEL1 sequence (summarised in Figure). 3D structure analysis predicted the missense RTEL1 mutations would result in disturbance of the FeS cluster and/or interfere with DNA binding, destabilisation of the HD1, HD2 or the ARCH sub-domains of the helicase domain, or destabilisation of inter-domain interactions. One HML1 mutation occurred in a loop opposite the putative ligand binding site and the rest in the variable regions outside the conserved domains. RTEL1 variants were associated with TERT mutations in 4 patients, of which 3 were known pathogenetic and 1 novel TERT mutation with low telomerase activity on TRAP assay confirming its pathogenetic nature. Conclusions We show for the first time that heterozygous RTEL1 mutations occur in 4.4% of patients, most commonly in young patients with a hypocellular BM, and often a family history of BMF/malignancy, and less often with high risk MDS/AML. Abnormal clinical features were present in a third of patients, some similar to but others distinct from dyskeratosis congenita. Disclosures No relevant conflicts of interest to declare.
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Simon, Rachel A., Christy M. Finke, Terra L. Lasho, Christopher T. Schmitz, Jenna A. Fernandez, Eva M. Carmona-Porquera, Mark E. Wylam, et al. "Functional Testing of Variants of Uncertain Significance in TERC, TERT,and RTEL1 from Adult Patients with Telomere Biology Disorders." Blood 142, Supplement 1 (November 28, 2023): 1365. http://dx.doi.org/10.1182/blood-2023-190153.
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INTRODUCTION Telomere biology disorders (TBDs) are multisystem diseases caused by accelerated telomere shortening that can present with bone marrow failure and pulmonary fibrosis, among other abnormalities. TBD diagnosis is considered when average blood telomere length (TL) measured by clinical flowFISH is <1 st percentile and/or a pathogenic variant in telomere maintenance genes (most commonly TERT, TERC, RTEL1) is identified. Pathogenic variants in genes coding for the telomerase protein ( TERT) and RNA component ( TERC) decrease telomerase activity. Similarly, variants in RTEL1 result in defective unwinding of the t-loop at telomere ends, increasing the levels of free t-circles in cells. Variants in these genes are often classified as variants of uncertain significance (VUSs by ACMG criteria) with additional efforts needed for variant curation. To address this, we describe results of functional testing performed in TBD patients with VUSs involving TERT, TERC, and RTEL1. METHODS TBD suspected patients were identified through the Pre-Myeloid Cancer and Bone Marrow Failure Clinic (Mayo Clinic) where they underwent clinical flowFISH and genetic testing for TBD related genes. Informed consent was obtained with approval from the Mayo Clinic Institutional Review Board. Viable peripheral blood and bone marrow samples were collected along with age matched healthy volunteers. Telomerase activity was measured in samples with TERT and TERC variants through telomeric repeat amplification protocol (TRAP) assays using the TRAPeze XL Telomerase Detection Kit (MilliporeSigma) following manufacturer instructions. HCT116 cells were used as positive controls while heat inactivated samples served as negative controls. Fluorescence was measured in a SpectraMax plate reader. Percentage of total product generated (TPG) relative to healthy age matched controls was calculated. T-circle detection assays were used on RTEL1 samples based on the protocol by Zhang et al. (2017). Final southern blotting was completed using the TeloTAGGG Telomere Length Assay Kit (Roche), and t-circle bands were visualized in a c600 GEL Imaging System (Azure Biosystems). RESULTS Ten patients (mean age = 53 years (27-71), 50% female) were included in our study. Patients 1 to 5 presented VUS in TERT (n=4) or TERC (n=1) and TL <1 st percentile in lymphocytes and/or granulocytes. Patient 6 carried a known pathogenic variant in RTEL1 and was included as a positive control. Patients 7 to 9 with RTEL1 variants presented TL close to the 10 th or between the 1 st-10 th percentile. No TL results were available for patient 10 but was tested due to the presence of a VUS in RTEL1 (Table 1). Similarly, while patient 7 carried a likely pathogenic variant, it was tested due to presenting lymphocyte TL between the 1 st-10 th percentile. TRAP results indicated decreased telomerase activity compared to age matched controls in all samples with TERT and TERC variants suggesting a pathogenic effect (52.%, 10.7%, 48.7%, 4.4% and 5.2% of TPG compared to age matched controls, respectively) (Table 1). On the other hand, t-circles were only seen in patient 6 (Figure 2). DISCUSSION We used TRAP and t-circle assays to explore the telomerase activity and presence of t-circles in patient samples with TERT/TERC and RTEL1 variants. In the case of TERT/TERC, we observed a reduction of telomerase activity in all samples. Together with blood TL below the 1 st percentile, this suggests that these variants are indeed deleterious (Table 1). However, since patient 4 presented two TERT VUSs, additional testing is needed to conclude how each variant impacts telomerase activity independently. In regard to RTEL1 variants, we observed t-circles in patient 6 as expected. No t-circles could be seen on all remaining samples, including patient 7 who carried a variant classified as likely pathogenic (Figure 1). This in-frame deletion has been described once in a TBD family (Cogan et al. 2015) but was not functionally tested. This result, together with the borderline TL seen in this patient, may suggest that some compensatory mechanism exists on this sample, or that the deleterious effect of the variant is not strong enough to be detected by our assay. Further studies are currently ongoing by our group to validate these results using a cell-based transfection disease model. In summary, we show that functional testing can be a helpful tool to determine pathogenicity of VUSs in TERT/TERC and RTEL1.
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&NA;. "RTEL1: the protector of the genome." Oncology Times UK 5, no. 11 (November 2008): 4. http://dx.doi.org/10.1097/01434893-200811000-00004.
Full textDissertations / Theses on the topic "RTEL1"
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Porreca, Rosa Maria. "The role of human RTEL1 in telomere maintenance." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066422.
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Rtel1 est une hélicase qui a été identifiée comme un facteur essentiel pour maintenir les télomères longs et le génome stable chez la souris. Chez l'homme, des mutations germinales dans RTEL1 ont été trouvées chez les patients atteints du syndrome de Hoyeraal-Hreidarsson (HHS), une forme grave de la dyskératose congénitale. Cependant, le mécanisme selon lequel cette protéine agit dans les cellules humaines reste en grande partie inconnu. Pour étudier la fonction de RTEL1 sur le métabolisme des télomères nous avons réduit l'expression de RTEL1 par ARN interférent dans plusieurs lignées de cellules humaines et analysé la longueur des télomères par quantitative-FISH. Nos résultats montrent que la dérégulation de RTEL1 induit un raccourcissement des télomères uniquement dans les cellules avec de très longs télomères et surexprimant la télomérase. Nous démontrons également que l'absence de RTEL1 provoque une altération du complexe de shelterin au télomères: l'augmentation des niveaux de TRF2 et la diminution de POT1. La surexpression de la portion OB fold de POT1 peut restaurer le raccourcissement des télomères causé par le knockdown de RTEL1. Ceci indique que RTEL1 peut jouer un rôle important dans la stabilité du 3' sortant et l'accessibilité de la télomérase. Nous constatons également un impact de RTEL1 sur le métabolisme de l'ARN non codant télomérique TERRA. En effet, la diminution de RTEL1 réduit la quantité totale de TERRA présente dans le noyau et en particulier de TERRA associé aux télomères. Nous constatons que ce nombre réduit de TERRA est causé par sa dégradation, donc nous proposons que RTEL1 a un rôle dans la stabilisation de TERRA aux télomèresRtel1, regulator of telomere elongation helicase 1, was discovered as an essential factor for telomere length maintenance and genomic stability in mice. In humans, germline mutations in RTEL1 have been found in patients with Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. However, the precise mechanism of action of the protein in human cells remains largely unknown. To investigate the function of RTEL1 in human telomere metabolism we used a knockdown approach by specific siRNAs and quantitative-FISH to measure telomere length after depletion of RTEL1 in different cancer cell lines. Our results show that down-regulation of RTEL1 induces shortening of telomeres only in cells with very long telomeres and high telomerase activity. We also demonstrate that upon depletion of RTEL1 there is a different stochiometry of shelterin proteins at telomeres: increased levels of TRF2 and decreased levels of POT1. Importantly, the overexpression of the POT1 OB fold can rescue the shortening of telomeres caused by the knockdown of RTEL1 indicating that RTEL1 may play an important role in the stability of the overhang and in its accessibility to telomerase. We also find an affect of RTEL1 on Telomeric non-coding RNA (TERRA) metabolism. Indeed, depletion of RTEL1 in human cell lines reduces the total amount of TERRA present in the nucleus and in particular of telomere-associated TERRA. Moreover, we find that this reduced number of UUAGGG repeats is caused by TERRA degradation, therefore we propose that RTEL1 has a role in stabilizing TERRA at telomeres
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Porreca, Rosa Maria. "The role of human RTEL1 in telomere maintenance." Electronic Thesis or Diss., Paris 6, 2014. http://www.theses.fr/2014PA066422.
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Rtel1 est une hélicase qui a été identifiée comme un facteur essentiel pour maintenir les télomères longs et le génome stable chez la souris. Chez l'homme, des mutations germinales dans RTEL1 ont été trouvées chez les patients atteints du syndrome de Hoyeraal-Hreidarsson (HHS), une forme grave de la dyskératose congénitale. Cependant, le mécanisme selon lequel cette protéine agit dans les cellules humaines reste en grande partie inconnu. Pour étudier la fonction de RTEL1 sur le métabolisme des télomères nous avons réduit l'expression de RTEL1 par ARN interférent dans plusieurs lignées de cellules humaines et analysé la longueur des télomères par quantitative-FISH. Nos résultats montrent que la dérégulation de RTEL1 induit un raccourcissement des télomères uniquement dans les cellules avec de très longs télomères et surexprimant la télomérase. Nous démontrons également que l'absence de RTEL1 provoque une altération du complexe de shelterin au télomères: l'augmentation des niveaux de TRF2 et la diminution de POT1. La surexpression de la portion OB fold de POT1 peut restaurer le raccourcissement des télomères causé par le knockdown de RTEL1. Ceci indique que RTEL1 peut jouer un rôle important dans la stabilité du 3' sortant et l'accessibilité de la télomérase. Nous constatons également un impact de RTEL1 sur le métabolisme de l'ARN non codant télomérique TERRA. En effet, la diminution de RTEL1 réduit la quantité totale de TERRA présente dans le noyau et en particulier de TERRA associé aux télomères. Nous constatons que ce nombre réduit de TERRA est causé par sa dégradation, donc nous proposons que RTEL1 a un rôle dans la stabilisation de TERRA aux télomèresRtel1, regulator of telomere elongation helicase 1, was discovered as an essential factor for telomere length maintenance and genomic stability in mice. In humans, germline mutations in RTEL1 have been found in patients with Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. However, the precise mechanism of action of the protein in human cells remains largely unknown. To investigate the function of RTEL1 in human telomere metabolism we used a knockdown approach by specific siRNAs and quantitative-FISH to measure telomere length after depletion of RTEL1 in different cancer cell lines. Our results show that down-regulation of RTEL1 induces shortening of telomeres only in cells with very long telomeres and high telomerase activity. We also demonstrate that upon depletion of RTEL1 there is a different stochiometry of shelterin proteins at telomeres: increased levels of TRF2 and decreased levels of POT1. Importantly, the overexpression of the POT1 OB fold can rescue the shortening of telomeres caused by the knockdown of RTEL1 indicating that RTEL1 may play an important role in the stability of the overhang and in its accessibility to telomerase. We also find an affect of RTEL1 on Telomeric non-coding RNA (TERRA) metabolism. Indeed, depletion of RTEL1 in human cell lines reduces the total amount of TERRA present in the nucleus and in particular of telomere-associated TERRA. Moreover, we find that this reduced number of UUAGGG repeats is caused by TERRA degradation, therefore we propose that RTEL1 has a role in stabilizing TERRA at telomeres
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Borie, Raphaël. "Génétique des fibroses pulmonaires familiales de l’adulte." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC208/document.
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Environ 10 % des patients atteints de fibrose pulmonaire idiopathique (FPI) ont au moins un apparenté atteint de pneumopathie interstitielle diffuse (PID). Des mutations avaient été mises en évidence sur les gènes codant pour les protéines impliquées dans le métabolisme du surfactant et les protéines du complexe télomérase. Chez l’adulte, les mutations de TERT étaient les plus fréquentes (˜15 %), les mutations de TERC, DKC1 et TINF2 plus rarement retrouvées. Environ 80 % des formes familiales de fibroses pulmonaires chez l’adulte étaient sans cause identifiée. Les objectifs de cette thèse étaient : 1) d’identifier un nouveau gène en cause dans les fibroses pulmonaires familiales de l’adulte inexpliquées, 2) de mieux caractériser le phénotype des patients présentant des mutations de TERT, de TERC ou du nouveau gène mis en évidence.Nous avons sélectionné 35 familles présentant une fibrose pulmonaire familiale pour lesquelles la recherche de mutation TERT, TERC, ABCA3, SFTPB et SFTPC était négative, pour réaliser un séquençage de l’exome. Quatre familles sur les 35 analysées présentaient un variant très rare sur RTEL1 à l’état hétérozygote. La présence des variants a été confirmée par séquençage selon la méthode de Sanger. Ces variants étaient absents des bases de données de contrôles. Les prédictions in silico étaient en faveur du caractère pathogène de ces variants. Les variants co-ségrégeaient avec la maladie dans les familles.L’analyse des variants à partir de la modélisation en 3D de la protéine suggérait un impact fonctionnel des variants sur le site de fixation à l’ATP ou à l’ADN. La taille des télomères des patients étaient raccourcies en comparaison des témoins de la même catégorie d’âge. En 2014, 237 patients avec une fibrose pulmonaire (153 avec une fibrose pulmonaire familiale, 84 avec un syndrome télomère) avaient bénéficié d’un séquençage de TERC et de TERT. Les variants ont été classés comme pathogènes chez 40 patients (16,8 %). Un âge de survenue précoce de fibrose, une macrocytose, ou une thrombopénie étaient significativement associée avec la présence d’une mutation. La probabilité d’une mutation était la plus importante pour les patients de 40-60 ans. La médiane de survie sans transplantation était plus faible pour les patients porteurs de mutations de TERT ou de TERC. Nous avons réalisé un séquençage de l’exome chez 40 autres familles et mis en évidence 5 nouveaux variants de RTEL1 probablement pathogènes in silico. Nous avons par ailleurs mis en évidence 3 autres mutations de RTEL1 dans une cohorte de PID associées à une polyarthrite rhumatoïde. Nous avons colligé les données de 35 patients atteints de PID et porteurs de mutations hétérozygotes de RTEL1. Vingt patients présentaient une FPI (57 %) et 10 une PID secondaire (25,7%). A la différence des mutations de TERT ou TERC, les mutations de RTEL1 étaient associées à moins d’anomalies hématologiques. Par ailleurs, l’expression pulmonaire de la protéine RTEL1 évaluée par immuno-histochimie et de l’ARNm par PCR était équivalente chez les patients porteurs de mutations RTEL1, de TERT ou atteints de FPI sans mutation. Nous avons identifié et confirmé l’implication d’un nouveau gène, RTEL1, dans environ 10 % des fibroses pulmonaires familiales. La présence d’une macrocytose, d’une thrombopénie ou d’un âge jeune en présence d’une forme familiale de fibrose est prédictive de la présence d’une mutation de TERT ou de TERC. La pénétrance des maladies hématologiques semble plus faible pour les mutations de RTEL1 que pour celles de TERT ou TERC dans notre cohorte recrutée sur l’atteinte pulmonaire. Les mutations de TERT ou de RTEL1 sont fréquemment associées à des PID secondairesAbout 10% of patients with idiopathic pulmonary fibrosis (IPF) have at least one relative with interstitial lung disease (ILD). Mutations had been reported on the genes encoding for the proteins involved in the surfactant metabolism and in the telomerase complex In adults, TERT mutations were the most frequent (˜15%), mutations of TERC, DKC1 and TINF2 more rarely found. Approximately 80% of the familial forms of pulmonary fibroses in adults were unidentified. The objectives of this work were: 1) to identify a new gene involved in unexplained adult familial pulmonary fibrosis, 2) to better characterize the phenotype of patients with mutations of TERT, TERC or the new gene detected. We selected 35 families with familial pulmonary fibrosis for which the TERT, TERC, ABCA3, SFTPB and SFTPC mutation search was negative, to perform exome sequencing. Four of the 35 families analyzed showed a very rare variant on RTEL1 in the heterozygous state. The presence of the variants was confirmed by Sanger sequencing. These variants were absent from the control databases. In silico predictions were in favor of the pathogenicity of these variants.In families, the variants co-segregated with the disease. In 3D modeling, analysis of the variants suggested a functional impact at the ATP or DNA binding site. The telomere length of carriers of the mutations was shortened compared to controls in the same age group. In 2014, 237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome) were sequenced for TERC and TERT. The variants were classified as pathogenic in 40 patients (16.8%). An early age of diangosis, macrocytosis, or thrombocytopenia were significantly associated with the presence of a mutation.The probability of a mutation was greatest for patients aged 40-60 years. The median survival without transplantation was lower for patients with TERT or TERC mutations.We performed a sequencing of the exoma in 40 other families and showed 5 new variants of RTEL1 probably pathogenic in silico. We also demonstrated 3 other mutations of RTEL1 in a cohort of ILD associated with rheumatoid arthritis. We collected data from 35 patients with ILD carriers of RTEL1 heterozygous mutations. Twenty patients had IPF (57%) and 10 a secondary ILD (25.7%). Unlike mutations within TERT or TERC, RTEL1 mutations were associated with fewer hematological abnormalities.Furthermore, the pulmonary expression of the RTEL1 protein evaluated by immunohistochemistry and mRNA by PCR was equivalent in patients carriers of RTEL1 or TERT mutations or IPF without mutation. We identified and confirmed the implication of a new gene, RTEL1, in about 10% of familial pulmonary fibroses. The presence of macrocytosis, thrombocytopenia or a young age is predictive of the presence of a mutation within TERT or TERC. The penetrance of hematological diseases appears to be lower for RTEL1 mutation carriers than for TERT or TERC mutation carriers in our cohort of ILD patient. Mutations of TERT or RTEL1 are frequently associated with secondary ILD
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Rodrigues, Fernanda Gutierrez. "Identificação de moduladores genéticos em pacientes com anemia aplástica por sequenciamento de nova geração." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17154/tde-25072018-110641/.
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A fisiopatologia das síndromes de falência da medula óssea (FMO) está relacionada a mecanismos adquiridos de destruição das células-tronco hematopoeiticas na medula ou a defeitos constitucionais em genes fundamentais para o reparo do DNA e manutenção dos telômeros. A anemia aplástica (AA), o protótipo das doenças de FMO, pode ter etiologia adquirida ou constitucional. A avaliação genética de pacientes com AA adquirida tem como objetivo a detecção de mutações somáticas que possam ser usadas como marcadores de resposta ao tratamento imunossupressor. Diferentemente, em pacientes com AA constitucional, a avaliação genética é fundamental para detecção de mutações etiológicas na doença do paciente, sendo essencial para o tratamento e seleção de doadores de medula óssea. Contudo, o papel das mutações constitucionais na fisiopatologia e modulação imunológica da AA adquirida ainda não é conhecido. Neste estudo, nós sequenciamos pacientes com AA de duas coortes independentes utilizando diferentes painéis de sequenciamento de genes alvos. A primeira coorte, composta por 13 pacientes com AA adquirida, foi sequenciada utilizando um painel com 165 genes relacionados à FMO, neoplasias hematológicas, reparo de DNA, manutenção dos telômeros e vias de resposta imune. A segunda coorte, composta por 59 pacientes investigados para doença constitucional, foi sequenciada com um painel de sequenciamento comercial com 49 genes relacionados à FMO hereditária. Foram identificadas alterações potencialmente patogênicas em três dos cinco pacientes com AA adquirida que não responderam à imunossupressão: dois pacientes com variantes em TERT e um com uma variante em DHX36. Não foram identificadas variantes funcionalmente relevantes nos pacientes que responderam ao tratamento imunossupressor. Em contraste, foram identificadas variantes potencialmente patogênicas em RTEL1 em 8 pacientes com AA constitucional. Variantes em RTEL1 foram associadas tanto ao encurtamento telomérico quanto à erosão excessiva do 3\' overhang, independentemente do comprimento dos telômeros. Desse modo, apenas a medida do comprimento dos telômeros não foi suficiente para identificar todos ospacientes com disfunções teloméricas. As plataformas de sequenciamento de nova geração diminuíram o custo e o tempo para a avaliação genética dos pacientes com FMO. Em nosso estudo, os pacientes com AA adquirida não apresentaram um padrão genético associado à sua resposta ao tratamento com imunossupressores, no entanto, o sequenciamento da coorte com suspeita de AA constitucional foi capaz de identificar o defeito genético associado à doença do paciente em 40% dos casos. O uso de dados clínicos, investigação familiar, análises in silico e testes funcionais foram essenciais para uma correta interpretação da patogenicidade de novas variantes identificadas por sequenciamento de nova geração.The pathophysiology of bone marrow failure (BMF) can be immune, as in acquired aplastic anemia (AA), or constitutional, due to germline mutations in genes critical for DNA repair and telomere maintenance. The genetic screening of patients with constitutional AA is performed to detect germline mutations that are etiologic in patients\' disease. That is critical for treatment decisions and to identify a donor for a bone marrow transplant. In acquired AA, the genetic screening has been used to detect somatic mutations that can predict patients\' outcomes after treatment, as the role of germline mutations in this disease is yet not clear. To investigate the role of germline variants in AA, we screened two independent cohorts with two different targeting sequencing panels; a first cohort composed by 13 patients with acquired AA that was screened using a panel with 165 genes related to BMF, hematologic malignancies, DNA repair, telomere maintenance, and immune response pathways. A second cohort composed of 59 patients suspected to have a constitutional disease screened by a commercial Inherited Bone Marrow Failure Sequencing panel. In our first cohort, while patients without functional relevant germline variants responded to immunosuppression treatment (n=8), three out of 5 nonresponder patients were identified with variants in telomere biology genes. We found patients carrying TERT and DHX36 variants. In our constitutional AA cohort, we identified 8 patients carrying variants in the RTEL1 gene, a helicase critical to telomere maintenance. RTEL1 variants associated with both patients\' overall telomere shortening and single-stranded 3\' overhang erosion independent of telomere length. Also, 3\' overhang erosion was associated with patients\' predisposition to clonal evolution. In this context, the variants identified in the helicases genes DHX36 and RTEL1 were both associated with patients\' normal telomere length and poor outcomes. Also, telomere length measurement alone was insufficient to identify all primary telomere defects. The platforms of next-generation sequencing decreased the cost and time for the genetic screening of patients with BMF. In our study, acquired AA patients did not display a clear genetic pattern associated with their immunosuppressive treatment response. In contrast, the sequencing of the cohort selected based on their suspicion to have an inherited diseaseidentified a molecular defect that might be pathogenic in up to 40% of patients, including the RTEL1 variants. Pathogenicity assessment of genetic variants requires a combination of clinical, in silico, and functional data required to avoid misinterpretation of common variants.
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Recker, Julia [Verfasser], and H. [Akademischer Betreuer] Puchta. "Rolle der Helikase RTEL1 in DNA-Reparatur, Rekombination sowie in der Telomerstabilität in Arabidopsis thaliana / Julia Recker. Betreuer: H. Puchta." Karlsruhe : KIT-Bibliothek, 2014. http://d-nb.info/1066736766/34.
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Rivarola, Maximo Lisandro. "Insights into the regulation of ethylene receptor signaling by RTE1." College Park, Md.: University of Maryland, 2008. http://hdl.handle.net/1903/8784.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2008.Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Youngson, Neil Alexander. "Characterisation, epigenetic regulation and genome function of the imprinted mouse Rtl1 gene and related genes." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614915.
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Sehki, Hayat. "Rôle d’un suppresseur endogène de RNAi dans le développement de la plante et ses interactions avec les pathogènes." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASB034.
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Le Post-Transcriptional Gene Silencing (PTGS) est un mécanisme dirigé contre les acides nucléiques invasifs endogènes (transposons) et exogènes (pathogènes, transgènes). Dans le cas des virus, le PTGS peut s’attaquer aux ARNs double-brin (dsRNAs) intermédiaires de la réplication virale et aux ARNs simple-brin viraux, mais il est souvent inhibé par des protéines virales appelées Viral Suppressor of RNAi (VSR). Chez la plante modèle Arabidopsis thaliana, une enzyme appelée RNase THREE-LIKE 1 (RTL1) est induite en réponse à l'infection virale et détruit les dsRNAs de manière non sélective. Cette enzyme devrait assurer à la plante une seconde ligne de défense en clivant les dsRNAs viraux, mais les VSR qui inhibent le PTGS inhibent généralement RTL1, indiquant que les virus ont mis en place des outils capables de combattre simultanément ces deux mécanismes de défense. Toutefois, un virus, le Turnip yellow mosaic virus (TYMV), est incapable d’inhiber RTL1 et semble même tirer profit de RTL1 pour réussir à infecter A. thaliana (Shamandi et al., 2015).Au cours de cette thèse, nous avons approfondi l’étude de l’interaction Arabidopsis-TYMV. Nous avons montré que le TYMV est incapable d’inhiber l’exécution du PTGS, mais est toutefois capable d’inhiber l’étape d’amplification du PTGS. Cette action est due à la protéine virale P69, et nous avons montré que P69 est retrouvée dans des corpuscules cytoplasmiques appelés siRNA-bodies qui sont le siège de l’amplification du PTGS. Par ailleurs, nous avons généré des mutants rtl1 et montré que l’absence de RTL1 retarde l’infection par le TYMV et augmente la quantité de siRNAs dirigés contre le virus, tandis que la surexpression de RTL1 favorise l’infection et inhibe la production des siRNAs anti-viraux. Nous avons observé que RTL1 était retrouvée dans les siRNA-bodies, et nous avons montré que RTL1 était capable de détruire non seulement les dsRNAs mais également les siRNAs. Ces résultats indiquent donc que le TYMV réussit à infecter A. thaliana en : i) se répliquant dans des invaginations de la membrane chloroplastique (Prod’homme et al., 2003) qui mettent vraisemblablement les dsRNAs intermédiaires de la réplication à l’abri du PTGS et de RTL1, ii) en induisant l’expression de RTL1 qui s’attaque aux dsRNAs et siRNAs induits par le PTGS dans les siRNA-bodies en réponse à l’infection, et iii) en exprimant la protéine P69 qui complète l’action de RTL1 en inhibant l’amplification du PTGS résiduel.Malgré un effet neutre ou négatif pour la plante vis-à-vis des virus, RTL1 est conservé dans toutes les accessions d’Arabidopsis, et l’étude du ratio des mutations synonymes et non synonymes dans les gènes RTL1 de 42 Eucotylédones suggère que RTL1 subit une pression de sélection de conservation, suggérant un rôle essentiel. Chez A. thaliana, RTL1 est exprimé faiblement dans la racine, les tissus en sénescence, et au cours du développement de la graine. Le phénotypage des plantes sauvages et des mutants rtl1 n’a pas révélé de différences morphologiques notables, mais nous avons observé que le poids des graines était supérieur chez les mutants rtl1. Par ailleurs, nous avons observé une senescence accrue chez le mutant rtl1, en particulier dans l’accession Ler. Cette différence entre Ler et Col nous a poussé à examiner si RTL1 pouvait contribuer à la variabilité naturelle du PTGS des transgènes entre les accessions Ler (PTGS peu efficace) et Col (PTGS très efficace). Nous avons observé que la mutation rtl1 n’affectait pas sensiblement l’efficacité du PTGS chez Col mais augmentait celle de Ler au niveau de Col, ce qui pourrait s’expliquer par une plus forte expression de RTL1 chez Ler que chez Col. L’effet de l’absence de RTL1 devra donc être précisé en condition normale et en condition d’infection en privilégiant Ler plutôt que ColPost-Transcriptional Gene Silencing (PTGS) is a defense mechanism that targets invading nucleic acids of endogenous (transposons) or exogenous (pathogens, transgenes) origins. During virus infection, PTGS theoretically targets double-stranded (ds)RNA intermediates of viral replication and viral single-stranded RNAs; however, most viruses encode proteins, referred to as viral suppressor of RNAi (VSR), which inhibit PTGS. In the model plant Arabidopsis thaliana, an enzyme referred to as RNase THREE-LIKE 1 (RTL1) is induced in response to viral infection and cleaves dsRNAs in a non-specific manner. This enzyme should provide a second line of defense by cleaving viral dsRNAs, but VSR that inhibit PTGS generally inhibit RTL1, indicating that viruses had put in place tools that simultaneously counteract these two defense mechanisms. Nevertheless, at least one virus, Turnip yellow mosaic virus (TYMV), is not able to inhibit RTL1 and in fact seems to take advantage of RTL1 to successfully infect A. thaliana (Shamandi et al., 2015).In this thesis, we deepened the study of Arabidopsis-TYMV interaction. We show that TYMV is not able to inhibit PTGS execution but is able to inhibit PTGS amplification. This effect is due to the viral protein P69, and we show that P69 localizes in cytoplasmic foci called siRNA-bodies, where PTGS amplification takes place. Furthermore, using in house-generated rtl1 mutants, we show that the lack of RTL1 delays TYMV infection and promotes the production of siRNAs directed against the virus, whereas RTL1 overexpression enhances viral symptoms and suppresses the production of anti-viral siRNAs. We show that RTL1 is found in siRNA-bodies, and we show that RTL1 attacks not only dsRNAs but also siRNAs. These results indicate that, TYMV successfully infect A. thaliana by : i) replicating in chloroplast membrane invaginations (Prod’homme et al., 2003), which likely shelter dsRNAs intermediates of replication from PTGS and RTL1, ii) inducing RTL1 expression, which promotes the destruction of dsRNAs and siRNAs produced by PTGS in siRNA-bodies in response to TYMV infection, and iii) expressing the P69 protein to inhibit residual PTGS amplification.Despite a neutral or detrimental effect on plant anti-viral PTGS, RTL1 is conserved in all Arabidopsis accessions, and the study of synonymous and non-synonymous substitutions ratios in RTL1 genes from 42 dicotyledonous plant reveals that RTL1 is under the control of a conservative selection, suggesting an essential role. In A. thaliana, RTL1 is weakly expressed in roots, in senescent tissues and during seed development. Phenotyping wild-type plants and rtl1 mutants did not revealed any significant morphological differences, but we observed that seeds weight is enhanced in rtl1 mutants. Moreover, we observed an increased senescence in rtl1 mutants, in particular in the Ler accession. This difference between Ler and Col prompted us to determine if RTL1 could participate in the natural variability of transgene PTGS efficiency between Ler (weak PTGS) and Col (strong PTGS). We observed that rtl1 mutations have no significant effect on PTGS efficiency in Col, but enhances PTGS efficiency in Ler, up to the level of Col, which could be explained by a strongest RTL1 expression in Ler compared to Col. These results indicate that the effect of RTL1 impairment should be further examined in normal and infectious contexts by focusing on Ler rather than Col
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Riordan, Jesse Daniel. "A forward genetics approach to identify molecular drivers of liver cancer using Sleeping Beauty mouse models." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/5049.
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Each year liver cancer kills more than half a million people, making it the third
leading cause of cancer-related death worldwide. Annual incidence continues to rise steadily, both domestically and globally, increasing the burden of this disease. Advancements in the ability to obtain detailed molecular profiles of tumors have led to the successful development of targeted therapies for a number of different cancers. Unfortunately, however, the molecular pathogenesis of liver cancer is poorly understood relative to many other types of malignancies. Thus, the identification of factors contributing to the development and progression of liver tumors is a major goal of current research.
In pursuit of this goal, I have utilized the Sleeping Beauty (SB) transposon system as a tool for forward genetic mutagenesis screening in mice. The SB system recapitulates the kinetics of spontaneous tumor development in humans by providing a stepwise accumulation of mutations. Micro-evolutionary processes within a developing tumor lead to the selective expansion of cells harboring mutations that confer some kind of selective advantage. By identifying the most prevalent mutation events within a specific tumor type across a large number of independent samples, a list of genes implicated as being involved in tumorigenesis can be generated. Using this approach, the Dlk1-Dio3 imprinted domain was identified as a site of frequent mutation in SB-induced hepatocellular carcinomas (HCCs). I discovered that the mechanistic basis for recurrent selection of transposon insertion within this domain in liver tumors involved activated expression of Retrotransposon-like 1 (Rtl1). I also found that RTL1 activation is a common event in human HCC, suggesting that it could potentially be beneficial as a therapeutic target in a subset of patients.
Etiological factors related to liver cancer development are varied, but are linked by the fact that each provides a chronic liver injury stimulus that promotes the development of hepatic fibrosis. In fact, ˜ 90% of human HCC occurs in this context, and yet the majority of mouse liver cancer models fail to account for this important environmental component of the disease. I have conducted a screen for genetic drivers of liver cancer in the presence or absence of hepatic fibrosis. Comparison of mutation profiles between fibrotic and non-fibrotic tumors revealed largely non-overlapping sets of candidate genes, indicative of a differential selective pressure for mutations depending on the fibrotic context of the liver. Driver mutations identified preferentially in the presence of liver fibrosis have a high likelihood of relevance to human disease, given the similarities in environmental context and kinetics of mutation acquisition. Consistent with this idea, multiple genes with well-established roles in human HCC were found to be preferentially mutated in SB-induced tumors developed in a fibrotic liver.
Before a candidate cancer gene identified in an animal model system can have an impact on human disease, its proposed role in tumorigenesis must be validated. Existing techniques for validation of putative liver cancer genes suffer from significant limitations including high cost, low throughput, and a level of complexity that prohibits widespread utilization. I have contributed to the generation of a novel tool for in vivo validation of candidate genes that is not subject to these limitations. By combining elements of recombinant adenoviral vectors and the piggyBac transposition system, we have generated a highly flexible gene delivery system with significant advantages over existing techniques. The Ad-PB system has broad accessibility and applicability, making it a valuable tool for advancing efforts to improve cancer therapies.
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Seshadri, Nivedita. "To characterise the role of RTEL1 DNA helicase in the maintenance of intestinal stem/progenitor cells." 2015. http://hdl.handle.net/1993/30263.
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RTEL1 (Regulator of telomere length1) DNA helicase has been demonstrated to be vital for the maintenance of telomere length and genomic stability. However, its biological role during development is unknown. Our recent finding that RTEL1 is selectively expressed in several types of adult stem cells, suggests that RTEL1 could play an essential role in the maintenance of these cells. Depending on the function of RTEL1 in the maintenance of genomic stability, we hypothesize that RTEL1 could be required for protecting adult stem cells from genomic instability, whose dysfunction may not only impair tissue homeostasis/regeneration, but also could transform these cells to form tumors.
In this study, we have used mouse intestinal stem/progenitor cells model to address this hypothesis. With a transgenic lineage tracing assay, we demonstrated that RTEL1-expressing cells in intestinal crypts can self renew and differentiate to the progeny cells required for intestinal homeostasis. Using a conditional knockout approach, we also showed that loss of RTEL1 function could induce genomic instability in intestinal stem/progenitor cells, which significantly affected the survival of intestinal stem cells and intestinal regeneration. Finally, in this study, we also observed intestinal hyperplasia in our RTEL1 conditional knockout mice, indicating that loss of RTEL1 function may initiate intestinal tumorigenesis. All of these findings strongly support that RTEL1 could be one the key molecules necessary for the maintenance of intestinal stem/progenitor cells and this function could be important for preventing intestinal tumorigenesis.
Books on the topic "RTEL1"
1
Meyer, Rainer-Peter. Traumatologie am Schultergu rtel: 54 instruktive Fa lle : XD-US. Berlin [u.a.]: Springer Medizin, 2011.
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2
Michael, Valerie. Handbuch Lederarbeiten: [Anleitungen und Vorlagen fu r Taschen, Mappen, Bo rsen, Masken und Gu rtel]. Hannover: Verlag Th. Scha fer im Vincentz Network, 2008.
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Kerber and Theodor Corvey-Helmert. Inro. Das Ding Am G, Rtel. Kerber Christof Verlag, 1998.
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2020, Schwarzer Gurtel Kalender. Jemand Mit Schwarzem G�rtel Ist Jemand Mit Wei�em G�rtel der Niemals Aufgegeben Hat: Jahreskalender F�r das Jahr 2020 Din-A5 Format Jahresplaner. Independently Published, 2019.
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Notizbucher, Msed. Hausbautagebuch : Dokumentiere Deinen Traum Vom Eigenheim : ♦ Tagebuch F�r Alle Bauherren ♦ Erstelle T�gliche Bauberichte ♦ Mit Platz F�r Erinnerungen, Notizen Oder Fotos ♦ A4+ Format ♦ Motiv: M�rtel. Independently Published, 2019.
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Notizbucher, Msed. Hausbautagebuch : Dokumentiere Deinen Traum Vom Eigenheim : ♦ Tagebuch F�r Alle Bauherren ♦ Erstelle T�gliche Bauberichte ♦ Mit Platz F�r Erinnerungen, Notizen Oder Fotos ♦ 6x9 Format ♦ Motiv: M�rtel. Independently Published, 2019.
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Flores, Joel. Si Ellos Pueden ... �Por Qu� YO NO?: Si lo Pensantes, Entonces Convi�rtelo en una Realidad Palpitante con la Actitud Necesaria para Errar en la Vida Por Aquel Sue�o Inalcanzable. el Miedo y Las Dudas Roban Sue�os No Permitas Que Te Roben Los Tuyos. Independently Published, 2019.
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Sykes, K. "KBP-13." In Secretory Pathway, 86–87. Oxford University PressOxford, 1994. http://dx.doi.org/10.1093/oso/9780198599425.003.0052.
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Abstract The nucleotide sequence of the FKBP-13 gene cloned from human cells (GenBank accession #M65128} predicts a protein of 141 amino acids that includes an N-terminal hydrophobic region thought to constitute a 21 residue signal peptide712. A (-terminal tetrapeptide (RTEL) may serve as a ER retention (or retrieval) sequence7 There is 55% amino acid sequence identity between the mature FKBP-13 proteins isolated from human cells and yeast, and 44% identity between FKBP-13 and the major cytoplasmic FKBP (FKBP-12) of human cells. A central region of marked homology among the several FKBP family members coincides with the drug binding and enzyme active site defined in FKBP-12.
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Basak, Rohini, Sudip Kumar Naskar, and Alexander Gelbukh. "A Lexico-Syntactic-Semantic Approach to Recognizing Textual Entailment." In Advances in Computational Intelligence and Robotics, 187–227. IGI Global, 2020. http://dx.doi.org/10.4018/978-1-7998-3038-2.ch010.
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Given two textual fragments, called a text and a hypothesis, respectively, recognizing textual entailment (RTE) is a task of automatically deciding whether the meaning of the second fragment (hypothesis) logically follows from the meaning of the first fragment (text). The chapter presents a method for RTE based on lexical similarity, dependency relations, and semantic similarity. In this method, called LSS-RTE, each of the two fragments is converted to a dependency graph, and the two obtained graph structures are compared using dependency triple matching rules, which have been compiled after a thorough and detailed analysis of various RTE development datasets. Experimental results show 60.5%, 64.4%, 62.8%, and 61.5% accuracy on the well-known RTE1, RTE2, RTE3, and RTE4 datasets, respectively, for the two-way classification task and 54.3% accuracy for three-way classification task on the RTE4 dataset.
Conference papers on the topic "RTEL1"
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Winters, N., C. Calvi, C. Habermann, H. Ding, T. S. Blackwell, and J. Kropski. "Role of Regulator of Telomere Elongation Helicase 1 (RTEL1) in Experimental Models of Pulmonary Fibrosis." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a1242.
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Li, Xun, and Wei-Ping Huang. "Hierarchical Modeling of Semiconductor Distributed-feedback Laser Diodes." In Integrated Photonics Research. Washington, D.C.: OSA, 1999. http://dx.doi.org/10.1364/ipr.1999.rtul1.
Full textReports on the topic "RTEL1"
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Chang, Caren. RTE1, A Novel Regulator of Ethylene Receptor Function. Office of Scientific and Technical Information (OSTI), February 2013. http://dx.doi.org/10.2172/1062076.
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