Journal articles: 'DDX17'

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Nelson, Corey R., Tyler Mrozowich, Sean M. Park, Simmone D’souza, Amy Henrickson, Justin R. J. Vigar, Hans-Joachim Wieden, Raymond J. Owens, Borries Demeler, and Trushar R. Patel. "Human DDX17 Unwinds Rift Valley Fever Virus Non-Coding RNAs." International Journal of Molecular Sciences 22, no. 1 (December 23, 2020): 54. http://dx.doi.org/10.3390/ijms22010054.

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Rift Valley fever virus (RVFV) is a mosquito-transmitted virus from the Bunyaviridae family that causes high rates of mortality and morbidity in humans and ruminant animals. Previous studies indicated that DEAD-box helicase 17 (DDX17) restricts RVFV replication by recognizing two primary non-coding RNAs in the S-segment of the genome: the intergenic region (IGR) and 5′ non-coding region (NCR). However, we lack molecular insights into the direct binding of DDX17 with RVFV non-coding RNAs and information on the unwinding of both non-coding RNAs by DDX17. Therefore, we performed an extensive biophysical analysis of the DDX17 helicase domain (DDX17135–555) and RVFV non-coding RNAs, IGR and 5’ NCR. The homogeneity studies using analytical ultracentrifugation indicated that DDX17135–555, IGR, and 5’ NCR are pure. Next, we performed small-angle X-ray scattering (SAXS) experiments, which suggested that DDX17 and both RNAs are homogenous as well. SAXS analysis also demonstrated that DDX17 is globular to an extent, whereas the RNAs adopt an extended conformation in solution. Subsequently, microscale thermophoresis (MST) experiments were performed to investigate the direct binding of DDX17 to the non-coding RNAs. The MST experiments demonstrated that DDX17 binds with the IGR and 5’ NCR with a dissociation constant of 5.77 ± 0.15 µM and 9.85 ± 0.11 µM, respectively. As DDX17135–555 is an RNA helicase, we next determined if it could unwind IGR and NCR. We developed a helicase assay using MST and fluorescently-labeled oligos, which suggested DDX17135–555 can unwind both RNAs. Overall, our study provides direct evidence of DDX17135–555 interacting with and unwinding RVFV non-coding regions.

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Samaan, Samaan, Léon-Charles Tranchevent, Etienne Dardenne, Micaela Polay Espinoza, Eleonora Zonta, Sophie Germann, Lise Gratadou, Martin Dutertre, and Didier Auboeuf. "The Ddx5 and Ddx17 RNA helicases are cornerstones in the complex regulatory array of steroid hormone-signaling pathways." Nucleic Acids Research 42, no. 4 (November 25, 2013): 2197–207. http://dx.doi.org/10.1093/nar/gkt1216.

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Abstract Estrogen and androgen receptors (ER and AR) play key roles in breast and prostate cancers, respectively, where they regulate the transcription of large arrays of genes. The activities of ER and AR are controlled by large networks of protein kinases and transcriptional coregulators, including Ddx5 and its highly related paralog Ddx17. The Ddx5 and Ddx17 RNA helicases are also splicing regulators. Here, we report that Ddx5 and Ddx17 are master regulators of the estrogen- and androgen-signaling pathways by controlling transcription and splicing both upstream and downstream of the receptors. First, Ddx5 and Ddx17 are required downstream of ER and AR for the transcriptional and splicing regulation of a large number of steroid hormone target genes. Second, Ddx5 and Ddx17 act upstream of ER and AR by controlling the expression, at the splicing level, of several key regulators of ER and AR activities. Of particular interest, we demonstrate that Ddx5 and Ddx17 control alternative splicing of the GSK3β kinase, which impacts on both ER and AR protein stability. We also provide a freely available online resource which gives information regarding splicing variants of genes involved in the estrogen- and androgen-signaling pathways.

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Hirai, Yuya, Eisuke Domae, Yoshihiro Yoshikawa, and Keizo Tomonaga. "Differential roles of two DDX17 isoforms in the formation of membraneless organelles." Journal of Biochemistry 168, no. 1 (February 17, 2020): 33–40. http://dx.doi.org/10.1093/jb/mvaa023.

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Abstract The RNA helicase, DDX17 is a member of the DEAD-box protein family. DDX17 has two isoforms: p72 and p82. The p82 isoform has additional amino acid sequences called intrinsically disordered regions (IDRs), which are related to the formation of membraneless organelles (MLOs). Here, we reveal that p72 is mostly localized to the nucleoplasm, while p82 is localized to the nucleoplasm and nucleoli. Additionally, p82 exhibited slower intranuclear mobility than p72. Furthermore, the enzymatic mutants of both p72 and p82 accumulate into the stress granules. The enzymatic mutant of p82 abolishes nucleolar localization of p82. Our findings suggest the importance of IDRs and enzymatic activity of DEAD-box proteins in the intracellular distribution and formation of MLOs.

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Moy, Ryan H., and Sara Cherry. "DDX17: Structured RNA recognition drives diverse outputs." Cell Cycle 13, no. 22 (November 15, 2014): 3467–68. http://dx.doi.org/10.4161/15384101.2014.980695.

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Lin, Qi, Jian Cai, and Qin-Quan Wang. "The Significance of Circular RNA DDX17 in Prostate Cancer." BioMed Research International 2020 (August 21, 2020): 1–16. http://dx.doi.org/10.1155/2020/1878431.

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Circular RNA DDX17 (circDDX17) has been demonstrated as a tumor suppressor in colorectal cancer. However, mechanisms underlying circDDX17 effects in cases of prostate cancer (PCa) are not well understood. Thus, herein, we determined measures of circDDX17 expression by use of the TCGA database. Expression of circDDX17 in prostate cancer-afflicted tissue samples was determined by qRT-PCR. Functionally, circDDX17 induced remarkable inhibition of cell colonizing ability, invasion, and epithelial-mesenchymal transition (EMT) progression in vitro. Mechanistically, dual-luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down experiments helped verify interactions between circDDX17 and miR-346. Low expression of circDDX17 occurred in TCGA PCa samples. Furthermore, circDDX17 expression was downregulated significantly in PCa. These results suggested that circDDX17 suppressed PC cell mobility, proliferation, and invasion. Mechanistic experiments indicated that circDDX17 might serve as a ceRNA of miR-346 to relieve repressive effects of miR-346 upon phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP). LHPP expression itself was downregulated in TCGA PCa samples. Overall, our findings indicated that the circDDX17/miR-346/LHPP pathway inhibited the progression of prostate cancer and that circDDX17 may be a new potential therapeutic or diagnostic target for treating and diagnosing prostate cancer. As our study also demonstrated for the first time that LHPP might act as an anticancer gene in prostate cancer, the findings could have wide-ranging implications for the treatment of this affliction.

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Ngo, Tri D., Alexander C. Partin, and Yunsun Nam. "RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis." Cell Reports 29, no. 12 (December 2019): 4024–35. http://dx.doi.org/10.1016/j.celrep.2019.11.059.

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Moy, Ryan H., Brian S. Cole, Ari Yasunaga, Beth Gold, Ganesh Shankarling, Andrew Varble, Jerome M. Molleston, Benjamin R. tenOever, Kristen W. Lynch, and Sara Cherry. "Stem-Loop Recognition by DDX17 Facilitates miRNA Processing and Antiviral Defense." Cell 158, no. 4 (August 2014): 764–77. http://dx.doi.org/10.1016/j.cell.2014.06.023.

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Sourabh, Suman, Manish Chauhan, Rahena Yasmin, Sadaf Shehzad, Dinesh Gupta, and Renu Tuteja. "Plasmodium falciparum DDX17 is an RNA helicase crucial for parasite development." Biochemistry and Biophysics Reports 26 (July 2021): 101000. http://dx.doi.org/10.1016/j.bbrep.2021.101000.

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Urbanek-Trzeciak, Martyna, Edyta Jaworska, and Wlodzimierz Krzyzosiak. "miRNAmotif—A Tool for the Prediction of Pre-miRNA–Protein Interactions." International Journal of Molecular Sciences 19, no. 12 (December 17, 2018): 4075. http://dx.doi.org/10.3390/ijms19124075.

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MicroRNAs (miRNAs) are short, non-coding post-transcriptional gene regulators. In mammalian cells, mature miRNAs are produced from primary precursors (pri-miRNAs) using canonical protein machinery, which includes Drosha/DGCR8 and Dicer, or the non-canonical mirtron pathway. In plant cells, mature miRNAs are excised from pri-miRNAs by the DICER-LIKE1 (DCL1) protein complex. The involvement of multiple regulatory proteins that bind directly to distinct miRNA precursors in a sequence- or structure-dependent manner adds to the complexity of the miRNA maturation process. Here, we present a web server that enables searches for miRNA precursors that can be recognized by diverse RNA-binding proteins based on known sequence motifs to facilitate the identification of other proteins involved in miRNA biogenesis. The database used by the web server contains known human, murine, and Arabidopsis thaliana pre-miRNAs. The web server can also be used to predict new RNA-binding protein motifs based on a list of user-provided sequences. We show examples of miRNAmotif applications, presenting precursors that contain motifs recognized by Lin28, MCPIP1, and DGCR8 and predicting motifs within pre-miRNA precursors that are recognized by two DEAD-box helicases—DDX1 and DDX17. miRNAmotif is released as an open-source software under the MIT License. The code is available at GitHub (www.github.com/martynaut/mirnamotif). The webserver is freely available at http://mirnamotif.ibch.poznan.pl.

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Wu, Kou-Juey. "The role of miRNA biogenesis and DDX17 in tumorigenesis and cancer stemness." Biomedical Journal 43, no. 2 (April 2020): 107–14. http://dx.doi.org/10.1016/j.bj.2020.03.001.

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11

Jagdhane, P., S. Garg, J. Xia, L. He, D. Misiak, O. Mortusewicz, T. Helleday, C. Müller-Tidow, M. Koehn, and C. Pabst. "PF230 THE RNA HELICASE DDX17 PROTECTS ACUTE MYELOID LEUKEMIA CELLS AGAINST DNA DAMAGE." HemaSphere 3, S1 (June 2019): 67. http://dx.doi.org/10.1097/01.hs9.0000559136.77382.94.

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12

Fuller-Pace, Frances V. "The DEAD box proteins DDX5 (p68) and DDX17 (p72): Multi-tasking transcriptional regulators." Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1829, no. 8 (August 2013): 756–63. http://dx.doi.org/10.1016/j.bbagrm.2013.03.004.

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13

Asberger, Jasmin, Thalia Erbes, Markus Jaeger, Gerta Rücker, Claudia Nöthling, Andrea Ritter, Kai Berner, Ingolf Juhasz-Böss, and Marc Hirschfeld. "Endoxifen and fulvestrant regulate estrogen-receptor α and related DEADbox proteins." Endocrine Connections 9, no. 12 (December 2020): 1156–67. http://dx.doi.org/10.1530/ec-20-0281.

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Breast cancer (BC) represents the most common type of cancer in females worldwide. Endocrine therapy evolved as one of the main concepts in treatment of hormone-receptor positive BC. Current research focuses on the elucidation of tumour resistance mechanisms against endocrine therapy. In a translational in vitro approach, potential regulatory effects of clinically implemented BC anti-oestrogens on ERα, its coactivators DDX5, DDX17 and other DEADbox proteins as well as on the proliferation markers cyclin D1 and Ki67 were investigated on both the RNA and protein level. BC in vitro models for hormone-receptor positive (MCF-7, T-47D) and hormone-receptor negative cells (BT-20) were subjected to endocrine therapy. Anti-oestrogen-dependent expression regulation of target genes on the transcriptional and translational level was quantified and statistically assessed. Endocrine therapy decreases the expression levels of Ki67, cyclin D1 and ERα in hormone-receptor positive cells. In the hormone-receptor negative cells, the three parameters remained stable after endocrine therapy. Endoxifen triggers a downregulation of DDX5 and DDX23 in MCF-7 cells. Fulvestrant treatment downregulates the expression levels of all investigated DEADbox proteins in MCF-7 cells. In T-47D cells, endoxifen and fulvestrant lead to a decrease of all target gene expression levels. Interestingly, endocrine therapy affects DEADbox RNA expression levels in BT-20 cells, too. However, this result could only be confirmed for DDX1, immunocytologically. The investigated DEADbox proteins appear to correlate with the oestrogen-dependent tumourigenesis in hormone-receptor positive BC and show expression alterations after endocrine treatment.

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Wong, Hao Yun, Jeroen A. A. Demmers, Karel Bezstarosti, J. Anton Grootegoed, and Albert O. Brinkmann. "DNA dependent recruitment of DDX17 and other interacting proteins by the human androgen receptor." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1794, no. 2 (February 2009): 193–98. http://dx.doi.org/10.1016/j.bbapap.2008.11.001.

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Wu, Cheng-Yu, and Peter D. Nagy. "Blocking tombusvirus replication through the antiviral functions of DDX17-like RH30 DEAD-box helicase." PLOS Pathogens 15, no. 5 (May 28, 2019): e1007771. http://dx.doi.org/10.1371/journal.ppat.1007771.

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Fuller-Pace, Frances V., and Simak Ali. "The DEAD box RNA helicases p68 (Ddx5) and p72 (Ddx17): novel transcriptional co-regulators." Biochemical Society Transactions 36, no. 4 (July 22, 2008): 609–12. http://dx.doi.org/10.1042/bst0360609.

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DEAD box [a motif named after its amino acid sequence (Asp-Glu-Ala-Asp)] RNA helicases are known to play key roles in all cellular processes that require modulation of RNA structure. However, in recent years, several of these proteins have been found to function in transcriptional regulation. In the present paper, we shall review the literature demonstrating the action of p68 and, where data are available, p72 as transcriptional co-regulators for a range of transcription factors, namely ERα (oestrogen receptor α), the tumour suppressor p53, the myogenic regulator MyoD and Runx2, a transcription factor essential for osteoblast development. We shall also discuss evidence indicating that, in some cases at least, p68 and p72 have distinct, non-redundant, roles.

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Giraud, Guillaume, Sophie Terrone, and Cyril F. Bourgeois. "Functions of DEAD box RNA helicases DDX5 and DDX17 in chromatin organization and transcriptional regulation." BMB Reports 51, no. 12 (December 31, 2018): 613–22. http://dx.doi.org/10.5483/bmbrep.2018.51.12.234.

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Dardenne, Etienne, Micaela Polay Espinoza, Laurent Fattet, Sophie Germann, Marie-Pierre Lambert, Helen Neil, Eleonora Zonta, et al. "RNA Helicases DDX5 and DDX17 Dynamically Orchestrate Transcription, miRNA, and Splicing Programs in Cell Differentiation." Cell Reports 7, no. 6 (June 2014): 1900–1913. http://dx.doi.org/10.1016/j.celrep.2014.05.010.

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Hitachi, Keisuke, and Kunihiro Tsuchida. "Data describing the effects of depletion of Myoparr, myogenin, Ddx17, and hnRNPK in differentiating C2C12 cells." Data in Brief 25 (August 2019): 104172. http://dx.doi.org/10.1016/j.dib.2019.104172.

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Lorgeoux, René-Pierre, Qinghua Pan, Yann Le Duff, and Chen Liang. "DDX17 promotes the production of infectious HIV-1 particles through modulating viral RNA packaging and translation frameshift." Virology 443, no. 2 (September 2013): 384–92. http://dx.doi.org/10.1016/j.virol.2013.05.026.

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Geißler, Verena, Simone Altmeyer, Benjamin Stein, Heike Uhlmann-Schiffler, and Hans Stahl. "The RNA helicase Ddx5/p68 binds to hUpf3 and enhances NMD of Ddx17/p72 and Smg5 mRNA." Nucleic Acids Research 41, no. 16 (June 20, 2013): 7875–88. http://dx.doi.org/10.1093/nar/gkt538.

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Connerty, Patrick, Sarah Bajan, Judit Remenyi, Frances V. Fuller-Pace, and Gyorgy Hutvagner. "The miRNA biogenesis factors, p72/DDX17 and KHSRP regulate the protein level of Ago2 in human cells." Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1859, no. 10 (October 2016): 1299–305. http://dx.doi.org/10.1016/j.bbagrm.2016.07.013.

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Chapus, F., M. Locatelli, J. Fresquet, B. Testoni, and F. Zoulim. "DEAD-box helicases DDX5 and DDX17 areinvolved in the fine tuning of hepatitis B virus minichromosome transcriptional regulation." Journal of Hepatology 68 (April 2018): S762. http://dx.doi.org/10.1016/s0168-8278(18)31788-4.

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Germann, S., L. Gratadou, E. Zonta, E. Dardenne, B. Gaudineau, M. Fougère, S. Samaan, M. Dutertre, S. Jauliac, and D. Auboeuf. "Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor." Oncogene 31, no. 42 (January 23, 2012): 4536–49. http://dx.doi.org/10.1038/onc.2011.618.

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Jalal, C., H. Uhlmann-Schiffler, and H. Stahl. "Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation." Nucleic Acids Research 35, no. 11 (May 7, 2007): 3590–601. http://dx.doi.org/10.1093/nar/gkm058.

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Lambert, Marie-Pierre, Sophie Terrone, Guillaume Giraud, Clara Benoit-Pilven, David Cluet, Valérie Combaret, Franck Mortreux, Didier Auboeuf, and Cyril F. Bourgeois. "The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation." Nucleic Acids Research 46, no. 15 (June 21, 2018): 7686–700. http://dx.doi.org/10.1093/nar/gky545.

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Li, Kai, Chunfen Mo, Di Gong, Yan Chen, Zhao Huang, Yanyan Li, Jie Zhang, et al. "DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin." Cancer Letters 400 (August 2017): 194–202. http://dx.doi.org/10.1016/j.canlet.2017.02.029.

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Tabatabaeian, Hossein, Shen Kiat Lim, Tinghine Chu, Sock Hong Seah, and Yoon Pin Lim. "WBP2 inhibits microRNA biogenesis via interaction with the microprocessor complex." Life Science Alliance 4, no. 7 (June 11, 2021): e202101038. http://dx.doi.org/10.26508/lsa.202101038.

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WBP2 is an emerging oncoprotein with diverse functions in breast tumorigenesis via regulating Wnt, epidermal growth factor receptor, estrogen receptor, and Hippo. Recently, evidence shows that WBP2 is tightly regulated by the components of the miRNA biogenesis machinery such as DGCR8 and Dicer via producing both WBP2’s 3′UTR and coding DNA sequence-targeting miRNAs. This led us to hypothesize that WBP2 could provide a feedback loop to the biogenesis of its key upstream regulators by regulating the microprocessor complex activity. Indeed, WBP2 suppressed microprocessor activity by blocking the processing of pri-miRNAs to pre-miRNAs. WBP2 negatively regulated the assembly of the microprocessor complex via physical interactions with its components. Meta-analyses suggest that microprocessor complex components, in particular DGCR8, DDX5, and DEAD-Box Helicase17 (DDX17), have tumor-suppressive properties. 2D and 3D in vitro proliferation assays revealed that WBP2 blocked the tumor-suppressive properties of DGCR8, a key component of the microprocessor complex. In conclusion, WBP2 is a novel regulator of miRNA biogenesis that is a known dysregulated pathway in breast tumorigenesis. The reregulation of miRNA biogenesis machinery via targeting WBP2 protein may have implications in breast cancer therapy.

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Miro, Julie, Anne-Laure Bougé, Eva Murauer, Emmanuelle Beyne, Dylan Da Cunha, Mireille Claustres, Michel Koenig, and Sylvie Tuffery-Giraud. "First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene." International Journal of Molecular Sciences 21, no. 20 (October 21, 2020): 7803. http://dx.doi.org/10.3390/ijms21207803.

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The Duchenne muscular dystrophy (DMD) gene has a complex expression pattern regulated by multiple tissue-specific promoters and by alternative splicing (AS) of the resulting transcripts. Here, we used an RNAi-based approach coupled with DMD-targeted RNA-seq to identify RNA-binding proteins (RBPs) that regulate splicing of its skeletal muscle isoform (Dp427m) in a human muscular cell line. A total of 16 RBPs comprising the major regulators of muscle-specific splicing events were tested. We show that distinct combinations of RBPs maintain the correct inclusion in the Dp427m of exons that undergo spatio-temporal AS in other dystrophin isoforms. In particular, our findings revealed the complex networks of RBPs contributing to the splicing of the two short DMD exons 71 and 78, the inclusion of exon 78 in the adult Dp427m isoform being crucial for muscle function. Among the RBPs tested, QKI and DDX5/DDX17 proteins are important determinants of DMD exon inclusion. This is the first large-scale study to determine which RBP proteins act on the physiological splicing of the DMD gene. Our data shed light on molecular mechanisms contributing to the expression of the different dystrophin isoforms, which could be influenced by a change in the function or expression level of the identified RBPs.

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Vychytilova-Faltejskova, Petra, Alena Svobodova Kovarikova, Tomas Grolich, Vladimir Prochazka, Katerina Slaba, Tana Machackova, Jana Halamkova, et al. "MicroRNA Biogenesis Pathway Genes Are Deregulated in Colorectal Cancer." International Journal of Molecular Sciences 20, no. 18 (September 10, 2019): 4460. http://dx.doi.org/10.3390/ijms20184460.

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MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Each step of their production and maturation has to be strictly regulated, as any disruption of control mechanisms may lead to cancer. Thus, we have measured the expression of 19 genes involved in miRNAs biogenesis pathway in tumor tissues of 239 colorectal cancer (CRC) patients, 17 CRC patients with liver metastases and 239 adjacent tissues using real-time PCR. Subsequently, the expression of analyzed genes was correlated with the clinical-pathological features as well as with the survival of patients. In total, significant over-expression of all analyzed genes was observed in tumor tissues as well as in liver metastases except for LIN28A/B. Furthermore, it was shown that the deregulated levels of some of the analyzed genes significantly correlate with tumor stage, grade, location, size and lymph node positivity. Finally, high levels of DROSHA and TARBP2 were associated with shorter disease-free survival, while the over-expression of XPO5, TNRC6A and DDX17 was detected in tissues of patients with shorter overall survival and poor prognosis. Our data indicate that changed levels of miRNA biogenesis genes may contribute to origin as well as progression of CRC; thus, these molecules could serve as potential therapeutic targets.

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Ismael, Hala, Simone Altmeyer, and Hans Stahl. "Regulation of the U3-, U8-, and U13snoRNA Expression by the DEAD Box Proteins Ddx5/Ddx17 with Consequences for Cell Proliferation and Survival." Non-Coding RNA 2, no. 4 (September 30, 2016): 11. http://dx.doi.org/10.3390/ncrna2040011.

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Cargill, Michael, Rasika Venkataraman, and Stanley Lee. "DEAD-Box RNA Helicases and Genome Stability." Genes 12, no. 10 (September 23, 2021): 1471. http://dx.doi.org/10.3390/genes12101471.

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DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between genomic stability and several DEAD-box RNA helicase family proteins including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, and DDX41. For each helicase, we have reviewed evidence supporting their role in protecting the genome and their suggested mechanisms. Such helicases regulate the expression of factors promoting genomic stability, prevent DNA damage, and can participate directly in the response and repair of DNA damage. Finally, we summarized the pathological and therapeutic relationship between DEAD-box RNA helicases and cancer with respect to their novel role in genome stability.

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Alqahtani, H., K. Gopal, N. Gupta, K. Jung, A. Alshareef, X. Ye, F. Wu, L. Li, and R. Lai. "DDX17 (P72), a Sox2 binding partner, promotes stem-like features conferred by Sox2 in a small cell population in estrogen receptor-positive breast cancer." Cellular Signalling 28, no. 2 (February 2016): 42–50. http://dx.doi.org/10.1016/j.cellsig.2015.11.004.

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Sithole, Nyaradzai, Claire A. Williams, Aisling M. Vaughan, Julia C. Kenyon, and Andrew M. L. Lever. "DDX17 Specifically, and Independently of DDX5, Controls Use of the HIV A4/5 Splice Acceptor Cluster and Is Essential for Efficient Replication of HIV." Journal of Molecular Biology 430, no. 18 (September 2018): 3111–28. http://dx.doi.org/10.1016/j.jmb.2018.06.052.

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Emerson, Jillian M., Bradley M. Bartholomai, Carol S. Ringelberg, Scott E. Baker, Jennifer J. Loros, and Jay C. Dunlap. "period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock." Proceedings of the National Academy of Sciences 112, no. 51 (December 8, 2015): 15707–12. http://dx.doi.org/10.1073/pnas.1521918112.

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Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 [DEAD (Asp-Glu-Ala-Asp) Box Helicase 5] and DDX17 in humans and DBP2 (Dead Box Protein 2) in yeast, are implicated in various processes, including transcriptional regulation, elongation, and termination, ribosome biogenesis, and mRNA decay. Although prd-1 mutants display a long period (∼25 h) circadian developmental cycle, they interestingly display a WT period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator in the prd-1 mutant strain runs with a long period under glucose-sufficient conditions. Thus, PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein, and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose, PRD-1 is in the nucleus until glucose runs out, which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd-1 may be formally viewed as a clock mutant with defective nutritional compensation of circadian period length.

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Gao, Rongrong, Lijun Wang, Yihua Bei, Xiaodong Wu, Jiaqi Wang, Qiulian Zhou, Lichan Tao, Saumya Das, Xinli Li, and Junjie Xiao. "Long Noncoding RNA Cardiac Physiological Hypertrophy–Associated Regulator Induces Cardiac Physiological Hypertrophy and Promotes Functional Recovery After Myocardial Ischemia-Reperfusion Injury." Circulation 144, no. 4 (July 27, 2021): 303–17. http://dx.doi.org/10.1161/circulationaha.120.050446.

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Background: The benefits of exercise training in the cardiovascular system have been well accepted; however, the underlying mechanism remains to be explored. Here, we report the initial functional characterization of an exercise-induced cardiac physiological hypertrophy–associated novel long noncoding RNA (lncRNA). Methods: Using lncRNA microarray profiling, we identified lncRNAs in contributing the modulation of exercise-induced cardiac growth that we termed cardiac physiological hypertrophy–associated regulator (CPhar). Mice with adeno-associated virus serotype 9 driving CPhar overexpression and knockdown were used in in vivo experiments. Swim training was used to induce physiological cardiac hypertrophy in mice, and ischemia reperfusion injury surgery was conducted to investigate the protective effects of CPhar in mice. To investigate the mechanisms of CPhar’s function, we performed various analyses including quantitative reverse transcription polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), functional rescue experiments, mass spectrometry, in vitro RNA transcription, RNA pulldown, RNA immunoprecipitation, chromatin immunoprecipitation assay, luciferase reporter assay, and coimmunoprecipitation assays. Results: We screened the lncRNAs in contributing the modulation of exercise-induced cardiac growth through lncRNA microarray profiling and found that CPhar was increased with exercise and was necessary for exercise-induced physiological cardiac growth. The gain and loss of function of CPhar regulated the expression of proliferation markers, hypertrophy, and apoptosis in cultured neonatal mouse cardiomyocytes. Overexpression of CPhar prevented myocardial ischemia reperfusion injury and cardiac dysfunction in vivo. We identified DDX17 (DEAD-Box Helicase 17) as a binding partner of CPhar in regulating CPhar downstream factor ATF7 (activating transcription factor 7) by sequestering C/EBPβ (CCAAT/enhancer binding protein beta). Conclusions: Our study of this lncRNA CPhar provides new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of CPhar in the heart, and expanding our mechanistic understanding of lncRNA function, as well.

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Park, Jee Soo, Myung Eun Lee, Won Sik Jang, Koon Ho Rha, Seung Hwan Lee, Jongsoo Lee, and Won Sik Ham. "The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity." Cancers 13, no. 11 (May 24, 2021): 2574. http://dx.doi.org/10.3390/cancers13112574.

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Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.

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Jegadesan, Nanda Kumar, and Dana Branzei. "DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects." Proceedings of the National Academy of Sciences 118, no. 17 (April 20, 2021): e2024258118. http://dx.doi.org/10.1073/pnas.2024258118.

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DDX11 encodes an iron–sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug–resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.

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Yassin, Enas R., Anmaar M. Abdul-Nabi, Akiko Takeda, and Nabeel R. Yaseen. "Role of a Conserved Helicase Motif in the Transformation of Primary Human CD34+ Cells by the NUP98-DDX10 Oncogene." Blood 114, no. 22 (November 20, 2009): 2966. http://dx.doi.org/10.1182/blood.v114.22.2966.2966.

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Abstract Abstract 2966 Poster Board II-942 NUP98 gene rearrangements occur in acute myeloid leukemia and other hematopoietic malignancies, and result in the expression of fusion proteins. One of the most frequent NUP98 fusions is NUP98-DDX10 that consists of an N-terminal portion of NUP98 and a C-terminal segment of DDX10, a putative DEAD-box RNA helicase. Here we express NUP98-DDX10 in primary human CD34+ hematopoietic cells and show that it localizes within the nucleus in a punctate distribution. It dramatically increases the proliferation and self-renewal of primary human CD34+ cells and disrupts their erythroid and myeloid differentiation. Expression gene profiling shows dysregulation of many genes by NUP98-DDX10 in primary human CD34+ cells starting within 6 h. Comparison of the dysregulome of NUP98-DDX10 to that of another leukemogenic NUP98 fusion, NUP98-HOXA9, reveals a number of genes dysregulated by both oncoproteins, including HOX genes, COX-2, MYCN, angiopoietin-1, renin, HEY1, SOX4, and others, that may account for the induction of AML by these and other NUP98 fusion oncogenes. The HRAGRTAR sequence in the DDX10 portion of NUP98-DDX10 corresponds to a major motif shared by DEAD-box RNA helicases that is required for their ATP binding/hydrolysis, RNA-binding, and helicase functions. Mutating this motif diminished the transforming ability of NUP98-DDX10, indicating that it plays a role in leukemogenesis. These data demonstrate for the first time the transforming ability of NUP98-DDX10 and show that it is partially dependent on one of the consensus helicase motifs of DDX10. They also point to common pathways that may underlie leukemogenesis by different NUP98 fusions. Disclosures: No relevant conflicts of interest to declare.

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Abe, Takuya, Masato Ooka, Ryotaro Kawasumi, Keiji Miyata, Minoru Takata, Kouji Hirota, and Dana Branzei. "Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites." Proceedings of the National Academy of Sciences 115, no. 33 (July 30, 2018): 8412–17. http://dx.doi.org/10.1073/pnas.1803110115.

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Warsaw breakage syndrome, a developmental disorder caused by mutations in the DDX11/ChlR1 helicase, shows cellular features of genome instability similar to Fanconi anemia (FA). Here we report that DDX11-deficient avian DT40 cells exhibit interstrand crosslink (ICL)-induced chromatid breakage, with DDX11 functioning as backup for the FA pathway in regard to ICL repair. Importantly, we establish that DDX11 acts jointly with the 9-1-1 checkpoint clamp and its loader, RAD17, primarily in a postreplicative fashion, to promote homologous recombination repair of bulky lesions, but is not required for intra-S checkpoint activation or efficient fork progression. Notably, we find that DDX11 also promotes diversification of the chicken Ig-variable gene, a process triggered by programmed abasic sites, by facilitating both hypermutation and homeologous recombination-mediated gene conversion. Altogether, our results uncover that DDX11 orchestrates jointly with 9-1-1 and its loader, RAD17, DNA damage tolerance at sites of bulky lesions, and endogenous abasic sites. These functions may explain the essential roles of DDX11 and its similarity with 9-1-1 during development.

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Arai, Yasuhito, Fumie Hosoda, Hirofumi Kobayashi, Kyoko Arai, Yasuhide Hayashi, Nanao Kamada, Yasuhiko Kaneko, and Misao Ohki. "The inv(11)(p15q22) Chromosome Translocation of De Novo and Therapy-Related Myeloid Malignancies Results in Fusion of the Nucleoporin Gene, NUP98, With the Putative RNA Helicase Gene, DDX10." Blood 89, no. 11 (June 1, 1997): 3936–44. http://dx.doi.org/10.1182/blood.v89.11.3936.

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Abstract The inv(11)(p15q22) is a recurrent chromosomal abnormality associated with de novo and therapy-related myeloid malignancies. Here we report the molecular definition of this chromosomal aberration in four patients. Positional cloning showed the consistent rearrangement of the DDX10 gene on chromosome 11q22, which encodes a putative RNA helicase. The translocation targets the NUP98 gene on 11p15, a member of the FG peptide repeat nucleoporin family. In DDX10 and NUP98, the inv(11) breakpoints occurred within two introns of each gene and the two genes merged in-frame to produce the chimeric transcripts characteristic of this translocation. Although two reciprocal chimeric products, NUP98-DDX10 and DDX10-NUP98, were predicted, only NUP98-DDX10 appears to be implicated in tumorigenesis. DDX10 is predicted to be involved in ribosome assembly. NUP98 has been identified as a nuclear pore complex protein and a target of chromosomal translocation in acute myeloid leukemia through the t(7; 11)(p15; p15) translocation. The predicted NUP98-DDX10 fusion protein may promote leukemogenesis through aberrant nucleoplasmic transport of mRNA or alterations in ribosome assembly.

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Payne, Elspeth, Niccolo Bolli, Clemens Grabher, Jennifer Rhodes, John Kanki, Ilene Galinsky, Richard Stone, Finbar E. Cotter, and A. Thomas Look. "The Role of RNA Helicase Dead Box 18 in Zebrafish Hematopoiesis and Human MDS." Blood 112, no. 11 (November 16, 2008): 500. http://dx.doi.org/10.1182/blood.v112.11.500.500.

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Abstract Myelodysplasia (MDS) is a common condition characterized by ineffective and dysplastic hematopoiesis, peripheral blood cytopenias, and evolution to acute myeloid leukemia. Although the biology of MDS is heterogeneous, a common feature is the disruption of effective hematopoiesis, resulting from either reduced hematopoiesis (with hypocellular bone marrow) or ineffective hematopoiesis (with hypercellular bone marrow and increased intramedullary cell apoptosis). Our current understanding of the genetic pathways controlling human hematopoiesis, and how they are disrupted in MDS remains very limited. Non-random chromosomal deletions occur frequently i n patients with MDS. Such deletions are thought to inactivate tumor suppressor genes (TSGs) that contribute to the maintenance of normal myelopoiesis. Unfortunately, these inactivated TSGs remain largely unidentified. The zebrafish is a vertebrate model organism well suited to the phenotypic and genotypic investigation of MDS, since transcription factors and other proteins regulating hematopoiesis are conserved between zebrafish and humans. Genome-wide mutagenesis screens in zebrafish to assay for deficiencies in mature granulocytes can reveal novel genes involved in myelopoiesis and a subset of these genes may also be involved in the pathogenesis of MDS. The dead-box 18 protein (DDX18) is a member of the highly conserved dead-box family of DNA-dependant RNA helicases. DDX18 is a target of the MYC oncogene and the drosophila homologue pitchoune is involved in cell growth and proliferation. We conducted a recessive screen of viral insertional zebrafish mutants and found that the loss of ddx18 in zebrafish embryos significantly reduced numbers of myeloperoxidase- (mpo-) expressing cells at 2 days post-fertilization (dpf). We have confirmed that the myelopoietic phenotype results from the specific loss of ddx18 by using antisense morpholinos that disrupt transcription of ddx18. In addition to loss of mature myeloid cells, ddx18 mutant embryos showed reduced alpha-globin expression at 2dpf (as a marker of erythoid cells); as well as loss of expression of runx1 and c-myb at 36hpf, which are expressed in definitive hematopoietic stem cells (HSC) along the ventral wall of the zebrafish aorta. These data support the hypothesis that loss of myeloid and erythoid cells result from a reduction in hematopoietic stem cell numbers. To determine whether the reduction in mpo-expressing cells observed in ddx18 mutants resulted from diminished production or from increased cell death, we performed acridine orange and TUNEL staining. This demonstrated markedly increased cell death in ddx18 mutants. Flow cytometric assessment of whole embryo cell lysates for annexin V binding also confirmed increased numbers of apoptotic cells in ddx18 mutants at 2 dpf indicating that active cell death was occurring at this time point. Finally, injection of a morpholino to knockdown expression of p53 was able to rescue the reduction of mpo-expressing cells seen in ddx18 mutants and reverted myeloid cell numbers to that of WT siblings. Thus, loss of ddx18 results in p53-dependant cell death in hematopoietic cells. To address whether DDX18 in plays a role in human MDS/AML we sequenced the DDX18 gene in 22 human AML cell lines and patient samples from 72 patients. Three heterozygous nonsynonymous genomic DNA sequence alterations resulting in amino acid substitutions were detected in 2 MDS patients, C184Y and V371I in one patient and V621I in a second. None of these has been previously annotated as single nucleotide polymorphisms in any species. Two of the 3 alterations were located in regions conserved with the zebrafish ddx18 gene (C184 and V371). Our results demonstrate that ddx18 plays a critical role in developmental hematopoiesis in zebrafish. Infrequent DDX18 sequence alterations occur in human AML/MDS cells, suggesting that DDX18 disruption may have a role in the pathogenesis of AML/MDS in a subset of patients. Further studies will delineate the interaction between p53 and ddx18 in the zebrafish and address the functional consequences of the heterozygous mutations found in human AML/MDS samples to determine whether DDX18 can function as a novel tumor suppressor (and a potential therapeutic target) in MDS/AML.

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Simon, Anna K., Sandra Kummer, Sebastian Wild, Aleksandra Lezaja, Federico Teloni, Stanislaw K. Jozwiakowski, Matthias Altmeyer, and Kerstin Gari. "The iron–sulfur helicase DDX11 promotes the generation of single-stranded DNA for CHK1 activation." Life Science Alliance 3, no. 3 (February 18, 2020): e201900547. http://dx.doi.org/10.26508/lsa.201900547.

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The iron–sulfur (FeS) cluster helicase DDX11 is associated with a human disorder termed Warsaw Breakage Syndrome. Interestingly, one disease-associated mutation affects the highly conserved arginine-263 in the FeS cluster-binding motif. Here, we demonstrate that the FeS cluster in DDX11 is required for DNA binding, ATP hydrolysis, and DNA helicase activity, and that arginine-263 affects FeS cluster binding, most likely because of its positive charge. We further show that DDX11 interacts with the replication factors DNA polymerase delta and WDHD1. In vitro, DDX11 can remove DNA obstacles ahead of Pol δ in an ATPase- and FeS domain-dependent manner, and hence generate single-stranded DNA. Accordingly, depletion of DDX11 causes reduced levels of single-stranded DNA, a reduction of chromatin-bound replication protein A, and impaired CHK1 phosphorylation at serine-345. Taken together, we propose that DDX11 plays a role in dismantling secondary structures during DNA replication, thereby promoting CHK1 activation.

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Li, Lei, Elizabeth A. Monckton, and Roseline Godbout. "A Role for DEAD Box 1 at DNA Double-Strand Breaks." Molecular and Cellular Biology 28, no. 20 (August 18, 2008): 6413–25. http://dx.doi.org/10.1128/mcb.01053-08.

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ABSTRACT DEAD box proteins are a family of putative RNA helicases associated with all aspects of cellular metabolism involving the modification of RNA secondary structure. DDX1 is a member of the DEAD box protein family that is overexpressed in a subset of retinoblastoma and neuroblastoma cell lines and tumors. DDX1 is found primarily in the nucleus, where it forms two to four large aggregates called DDX1 bodies. Here, we report a rapid redistribution of DDX1 in cells exposed to ionizing radiation, resulting in the formation of numerous foci that colocalize with γ-H2AX and phosphorylated ATM foci at sites of DNA double-strand breaks (DSBs). The formation of DDX1 ionizing-radiation-induced foci (IRIF) is dependent on ATM, which was shown to phosphorylate DDX1 both in vitro and in vivo. The treatment of cells with RNase H prevented the formation of DDX1 IRIF, suggesting that DDX1 is recruited to sites of DNA damage containing RNA-DNA structures. We have shown that DDX1 has RNase activity toward single-stranded RNA, as well as ADP-dependent RNA-DNA- and RNA-RNA-unwinding activities. We propose that DDX1 plays an RNA clearance role at DSB sites, thereby facilitating the template-guided repair of transcriptionally active regions of the genome.

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Mahtab, Mohammad, Ana Boavida, Diana Santos, and Francesca M. Pisani. "The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer." Genes 12, no. 3 (March 10, 2021): 395. http://dx.doi.org/10.3390/genes12030395.

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DDX11/ChlR1 is a super-family two iron–sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named Warsaw breakage syndrome, characterized by a complex spectrum of clinical manifestations (pre- and post-natal growth defects, microcephaly, intellectual disability, heart anomalies and sister chromatid cohesion loss at cellular level) in accordance with the multifaceted, not yet fully understood, physiological functions of this DNA helicase. In the last few years, a possible role of DDX11 in the onset and progression of many cancers is emerging. Herein we summarize the results of recent studies, carried out either in tumoral cell lines or in xenograft cancer mouse models, suggesting that DDX11 may have an oncogenic role. The potential of DDX11 DNA helicase as a pharmacological target for novel anti-cancer therapeutic interventions, as inferred from these latest developments, is also discussed.

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Zhang, Hui, Jiangtao Lin, Junjun Chen, Wenqi Gu, Yanjie Mao, Haixia Wang, Yahui Zhang, and Wanjun Liu. "DDX11-AS1 contributes to osteosarcoma progression via stabilizing DDX11." Life Sciences 254 (August 2020): 117392. http://dx.doi.org/10.1016/j.lfs.2020.117392.

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Payne, Elspeth M., Niccolò Bolli, Jennifer Rhodes, Omar I. Abdel-Wahab, Ross Levine, Cyrus V. Hedvat, Richard Stone, et al. "Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML." Blood 118, no. 4 (July 28, 2011): 903–15. http://dx.doi.org/10.1182/blood-2010-11-318022.

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Abstract In a zebrafish mutagenesis screen to identify genes essential for myelopoiesis, we identified an insertional allele hi1727, which disrupts the gene encoding RNA helicase dead-box 18 (Ddx18). Homozygous Ddx18 mutant embryos exhibit a profound loss of myeloid and erythroid cells along with cardiovascular abnormalities and reduced size. These mutants also display prominent apoptosis and a G1 cell-cycle arrest. Loss of p53, but not Bcl-xl overexpression, rescues myeloid cells to normal levels, suggesting that the hematopoietic defect is because of p53-dependent G1 cell-cycle arrest. We then sequenced primary samples from 262 patients with myeloid malignancies because genes essential for myelopoiesis are often mutated in human leukemias. We identified 4 nonsynonymous sequence variants (NSVs) of DDX18 in acute myeloid leukemia (AML) patient samples. RNA encoding wild-type DDX18 and 3 NSVs rescued the hematopoietic defect, indicating normal DDX18 activity. RNA encoding one mutation, DDX18-E76del, was unable to rescue hematopoiesis, and resulted in reduced myeloid cell numbers in ddx18hi1727/+ embryos, indicating this NSV likely functions as a dominant-negative allele. These studies demonstrate the use of the zebrafish as a robust in vivo system for assessing the function of genes mutated in AML, which will become increasingly important as more sequence variants are identified by next-generation resequencing technologies.

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Pisani, Francesca, Ettore Napolitano, Luisa Napolitano, and Silvia Onesti. "Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11." Genes 9, no. 11 (November 21, 2018): 564. http://dx.doi.org/10.3390/genes9110564.

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DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability.

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Saeed, Mohammad, Alejandro Ibáñez-Costa, Alejandra María Patiño-Trives, Laura Muñoz-Barrera, Eduardo Collantes Estévez, María Ángeles Aguirre, and Chary López-Pedrera. "Expression of DDX11 and DNM1L at the 12p11 Locus Modulates Systemic Lupus Erythematosus Susceptibility." International Journal of Molecular Sciences 22, no. 14 (July 16, 2021): 7624. http://dx.doi.org/10.3390/ijms22147624.

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Objectives: This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. Methods: Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used. Confirmatory qPCR on SLE monocytes was performed. The entire 12p11 locus was investigated for genetic association using two additional GWAS. Expression of 150 genes at this locus was assessed. Based on this significance, qPCRs for DNM1L and KRAS were performed. Results: Fifty genes were differentially expressed in at least two SLE GEO-datasets, with all probes directionally aligned. DDX11, an RNA helicase involved in genome stability, was downregulated in both GEO and Cordoba datasets. The most significant SNP, rs3741869 in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression. DDX11 was found repressed. The entire 12p11 locus showed three association peaks. Gene expression in GEO datasets identified DNM1L and KRAS, besides DDX11. Confirmatory qPCR validated DNM1L as an SLE susceptibility gene. DDX11, DNM1L and KRAS interact with each other and multiple known SLE genes including STAT1/STAT4 and major components of IFN-dependent gene expression, and are responsible for signal transduction of cytokines, hormones, and growth-factors, deregulation of which is involved in SLE-development. Conclusion: A genomic convergence approach with OASIS analysis of multiple GWAS and expression datasets identified DDX11 and DNM1L as novel SLE-genes, the expression of which is altered in monocytes from SLE patients. This study lays the foundation for understanding the pathogenic involvement of DDX11 and DNM1L in SLE by identifying them using a systems-biology approach, while the 12p11 locus harboring these genes was previously missed by four independent GWAS.

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Zhou, Ya-Lan, Li-Xin Wu, Robert Peter Gale, Zi-Long Wang, Jin-Lan Li, Hao Jiang, Qian Jiang, et al. "Dead/H-Box Helicase 11 (DDX11) Mutations Correlate with Increased Relapse Risk in Persons with Acute Myeloid Leukaemia and Promote Proliferation and Survival of Human AML Cells in Vitro and in Immune Deficient Mice." Blood 134, Supplement_1 (November 13, 2019): 2732. http://dx.doi.org/10.1182/blood-2019-127831.

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Background About one-half of persons with acute myeloid leukemia have normal cytogenetics but have diverse outcomes which might be explained, at least in part, by specific mutations. We focused on DDX11, the budding yeast ortholog of ChlR1, which encodes an ATP-dependent RNA- and DNA-helicase involved in diverse cell processes such as sister chromatid exchange cohesions and implicated in other cancers and which is associated with telomere shortening. Methods DNA from 359 consecutive, newly-diagnosed adults with AML and normal cytogenetics were interrogated by deep target regional sequencing (TRS). Average effective sequencing depth was 1678.5X (1000.0-1800.0X) and median coverage, 99.9% (98.0, 100.0%). Outcomes studied included cumulative incidence of relapse (CIR) and event-free survival (EFS). DDX11 mutants were transfected into a human AML cell line which was studied in vitro and in immune deficient mice. Results We identified 2909 non-synonymous somatic variants. 284 subjects (79%; 95% confidence interval [CI], 75, 83%) had ≥5 mutations with a median of 8 mutations per subject (range, 1-20). We identified mutations at 4 new loci including DDX11 in 29 subjects (8%), NPIPA5 in 15 (4%), CYP2F1 in 13 (4%), and MED12 in 9 (3%). In multi-variable analyses DDX11 mutation was independently associated with CIR (Hazard Ratio [HR]= 2.276 [1.318, 3.931]; P=0.003) and EFS (HR=2.319 [1.391, 3.867], P=0.001). Two missense DDX11-mutant alleles (DDX11P316L/WT or DDX11Q363K/WT) were generated and introduced to the kasumi-1 leukemia cells by lentivirus transfection. Both mutants showed proliferative and anti-apoptotic activities in functional analyses and increased resistance to killing by Cytarabine and Daunorubicin in vitro and in transplanted immune deficient mice. Conclusions Subjects with AML with normal cytogenetics who have a DDX11 mutation have a higher CIR and worse EFS compared with subjects with wild-type DDX11. Functional studies of a transfected DDX11 human AML cell line provide a functional explanation of our clinical findings. * Correspondence Profs. Guo-Rui Ruan and Xiao-Jun Huang Peking University Peoples Hospital and Institute of Hematology No.11 Xi-Zhi-Men South Street, Beijing 100044, China T 86-10-88324672 F 86-10-88324672 E ruanguorui@pkuph.edu.cn OR huangxiaojun@bjmu.edu.cn Disclosures No relevant conflicts of interest to declare.

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Journal articles on the topic 'DDX17'

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