| Structural highlights
Function
[DDX17_HUMAN] As an RNA helicase, unwinds RNA and alters RNA structures through ATP binding and hydrolysis. Involved in multiple cellular processes, including pre-mRNA splicing, alternative splicing, ribosomal RNA processing and miRNA processing, as well as transcription regulation. Regulates the alternative splicing of exons exhibiting specific features (PubMed:12138182, PubMed:23022728, PubMed:24910439, PubMed:22266867). For instance, promotes the inclusion of AC-rich alternative exons in CD44 transcripts (PubMed:12138182). This function requires the RNA helicase activity (PubMed:12138182, PubMed:23022728, PubMed:24910439, PubMed:22266867). Affects NFAT5 and histone macro-H2A.1/H2AFY alternative splicing in a CDK9-dependent manner (PubMed:26209609, PubMed:22266867). In NFAT5, promotes the introduction of alternative exon 4, which contains 2 stop codons and may target NFAT5 exon 4-containing transcripts to nonsense-mediated mRNA decay, leading to the down-regulation of NFAT5 protein (PubMed:22266867). Affects splicing of mediators of steroid hormone signaling pathway, including kinases that phosphorylates ESR1, such as CDK2, MAPK1 and GSK3B, and transcriptional regulators, such as CREBBP, MED1, NCOR1 and NCOR2. By affecting GSK3B splicing, participates in ESR1 and AR stabilization (PubMed:24275493). In myoblasts and epithelial cells, cooperates with HNRNPH1 to control the splicing of specific subsets of exons (PubMed:24910439). In addition to binding mature mRNAs, also interacts with certain pri-microRNAs, including MIR663/miR-663a, MIR99B/miR-99b, and MIR6087/miR-6087 (PubMed:25126784). Binds pri-microRNAs on the 3' segment flanking the stem loop via the 5'-[ACG]CAUC[ACU]-3' consensus sequence (PubMed:24581491). Required for the production of subsets of microRNAs, including MIR21 and MIR125B1 (PubMed:24581491, PubMed:27478153). May be involved not only in microRNA primary transcript processing, but also stabilization (By similarity). Participates in MYC down-regulation at high cell density through the production of MYC-targeting microRNAs (PubMed:24581491). Along with DDX5, may be involved in the processing of the 32S intermediate into the mature 28S ribosomal RNA (PubMed:17485482). Promoter-specific transcription regulator, functioning as a coactivator or corepressor depending on the context of the promoter and the transcriptional complex in which it exists (PubMed:15298701). Enhances NFAT5 transcriptional activity (PubMed:22266867). Synergizes with TP53 in the activation of the MDM2 promoter; this activity requires acetylation on lysine residues (PubMed:17226766, PubMed:20663877, PubMed:19995069). May also coactivate MDM2 transcription through a TP53-independent pathway (PubMed:17226766). Coactivates MMP7 transcription (PubMed:17226766). Along with CTNNB1, coactivates MYC, JUN, FOSL1 and cyclin D1/CCND1 transcription (PubMed:17699760). Alone or in combination with DDX5 and/or SRA1 non-coding RNA, plays a critical role in promoting the assembly of proteins required for the formation of the transcription initiation complex and chromatin remodeling leading to coactivation of MYOD1-dependent transcription. This helicase-independent activity is required for skeletal muscle cells to properly differentiate into myotubes (PubMed:17011493, PubMed:24910439). During epithelial-to-mesenchymal transition, coregulates SMAD-dependent transcriptional activity, directly controlling key effectors of differentiation, including miRNAs which in turn directly repress its expression (PubMed:24910439). Plays a role in estrogen and testosterone signaling pathway at several levels. Mediates the use of alternative promoters in estrogen-responsive genes and regulates transcription and splicing of a large number of steroid hormone target genes (PubMed:24275493, PubMed:20406972, PubMed:20663877, PubMed:19995069). Contrary to splicing regulation activity, transcriptional coregulation of the estrogen receptor ESR1 is helicase-independent (PubMed:19718048, PubMed:24275493). Plays a role in innate immunity. Specifically restricts bunyavirus infection, including Rift Valley fever virus (RVFV) or La Crosse virus (LACV), but not vesicular stomatitis virus (VSV), in an interferon- and DROSHA-independent manner (PubMed:25126784). Binds to RVFV RNA, likely via structured viral RNA elements (PubMed:25126784). Promotes mRNA degradation mediated by the antiviral zinc-finger protein ZC3HAV1, in an ATPase-dependent manner (PubMed:18334637).[UniProtKB:Q501J6][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Publication Abstract from PubMed
DDX17, a DEAD-box ATPase, is a multifunctional helicase important for various RNA functions, including microRNA maturation. Key questions for DDX17 include how it recognizes target RNAs and influences their structures, as well as how its ATPase activity may be regulated. Through crystal structures and biochemical assays, we show the ability of the core catalytic domains of DDX17 to recognize specific sequences in target RNAs. The RNA sequence preference of the catalytic core is critical for DDX17 to directly bind and remodel a specific region of primary microRNAs 3' to the mature sequence, and consequently enhance processing by Drosha. Furthermore, we identify an intramolecular interaction between the N-terminal tail and the DEAD domain of DDX17 to have an autoregulatory role in controlling the ATPase activity. Thus, we provide the molecular basis for how cognate RNA recognition and functional outcomes are linked for DDX17.
RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis.,Ngo TD, Partin AC, Nam Y Cell Rep. 2019 Dec 17;29(12):4024-4035.e5. doi: 10.1016/j.celrep.2019.11.059. PMID:31851931[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Honig A, Auboeuf D, Parker MM, O'Malley BW, Berget SM. Regulation of alternative splicing by the ATP-dependent DEAD-box RNA helicase p72. Mol Cell Biol. 2002 Aug;22(16):5698-707. doi: 10.1128/mcb.22.16.5698-5707.2002. PMID:12138182 doi:http://dx.doi.org/10.1128/mcb.22.16.5698-5707.2002
- ↑ Wilson BJ, Bates GJ, Nicol SM, Gregory DJ, Perkins ND, Fuller-Pace FV. The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner. BMC Mol Biol. 2004 Aug 6;5:11. PMID:15298701 doi:http://dx.doi.org/10.1186/1471-2199-5-11
- ↑ Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P, Ogryzko V, Fuller-Pace FV, Hoffman EP, Tapscott SJ, Sartorelli V. The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. Dev Cell. 2006 Oct;11(4):547-60. PMID:17011493 doi:http://dx.doi.org/10.1016/j.devcel.2006.08.003
- ↑ Shin S, Janknecht R. Concerted activation of the Mdm2 promoter by p72 RNA helicase and the coactivators p300 and P/CAF. J Cell Biochem. 2007 Aug 1;101(5):1252-65. doi: 10.1002/jcb.21250. PMID:17226766 doi:http://dx.doi.org/10.1002/jcb.21250
- ↑ Jalal C, Uhlmann-Schiffler H, Stahl H. Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation. Nucleic Acids Res. 2007;35(11):3590-601. doi: 10.1093/nar/gkm058. Epub 2007 May, 7. PMID:17485482 doi:http://dx.doi.org/10.1093/nar/gkm058
- ↑ Shin S, Rossow KL, Grande JP, Janknecht R. Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res. 2007 Aug 15;67(16):7572-8. doi: 10.1158/0008-5472.CAN-06-4652. PMID:17699760 doi:http://dx.doi.org/10.1158/0008-5472.CAN-06-4652
- ↑ Chen G, Guo X, Lv F, Xu Y, Gao G. p72 DEAD box RNA helicase is required for optimal function of the zinc-finger antiviral protein. Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4352-7. doi:, 10.1073/pnas.0712276105. Epub 2008 Mar 11. PMID:18334637 doi:http://dx.doi.org/10.1073/pnas.0712276105
- ↑ Wortham NC, Ahamed E, Nicol SM, Thomas RS, Periyasamy M, Jiang J, Ochocka AM, Shousha S, Huson L, Bray SE, Coombes RC, Ali S, Fuller-Pace FV. The DEAD-box protein p72 regulates ERalpha-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERalpha-positive breast cancer. Oncogene. 2009 Nov 19;28(46):4053-64. doi: 10.1038/onc.2009.261. Epub 2009 Aug, 31. PMID:19718048 doi:http://dx.doi.org/10.1038/onc.2009.261
- ↑ Mooney SM, Grande JP, Salisbury JL, Janknecht R. Sumoylation of p68 and p72 RNA helicases affects protein stability and transactivation potential. Biochemistry. 2010 Jan 12;49(1):1-10. doi: 10.1021/bi901263m. PMID:19995069 doi:http://dx.doi.org/10.1021/bi901263m
- ↑ Dutertre M, Gratadou L, Dardenne E, Germann S, Samaan S, Lidereau R, Driouch K, de la Grange P, Auboeuf D. Estrogen regulation and physiopathologic significance of alternative promoters in breast cancer. Cancer Res. 2010 May 1;70(9):3760-70. doi: 10.1158/0008-5472.CAN-09-3988. Epub, 2010 Apr 20. PMID:20406972 doi:http://dx.doi.org/10.1158/0008-5472.CAN-09-3988
- ↑ Mooney SM, Goel A, D'Assoro AB, Salisbury JL, Janknecht R. Pleiotropic effects of p300-mediated acetylation on p68 and p72 RNA helicase. J Biol Chem. 2010 Oct 1;285(40):30443-52. doi: 10.1074/jbc.M110.143792. Epub 2010, Jul 27. PMID:20663877 doi:http://dx.doi.org/10.1074/jbc.M110.143792
- ↑ Germann S, Gratadou L, Zonta E, Dardenne E, Gaudineau B, Fougere M, Samaan S, Dutertre M, Jauliac S, Auboeuf D. Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor. Oncogene. 2012 Oct 18;31(42):4536-49. doi: 10.1038/onc.2011.618. Epub 2012 Jan, 23. PMID:22266867 doi:http://dx.doi.org/10.1038/onc.2011.618
- ↑ Dardenne E, Pierredon S, Driouch K, Gratadou L, Lacroix-Triki M, Espinoza MP, Zonta E, Germann S, Mortada H, Villemin JP, Dutertre M, Lidereau R, Vagner S, Auboeuf D. Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness. Nat Struct Mol Biol. 2012 Nov;19(11):1139-46. doi: 10.1038/nsmb.2390. Epub 2012, Sep 30. PMID:23022728 doi:http://dx.doi.org/10.1038/nsmb.2390
- ↑ Samaan S, Tranchevent LC, Dardenne E, Polay Espinoza M, Zonta E, Germann S, Gratadou L, Dutertre M, Auboeuf D. The Ddx5 and Ddx17 RNA helicases are cornerstones in the complex regulatory array of steroid hormone-signaling pathways. Nucleic Acids Res. 2014 Feb;42(4):2197-207. doi: 10.1093/nar/gkt1216. Epub 2013, Nov 25. PMID:24275493 doi:http://dx.doi.org/10.1093/nar/gkt1216
- ↑ Mori M, Triboulet R, Mohseni M, Schlegelmilch K, Shrestha K, Camargo FD, Gregory RI. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell. 2014 Feb 27;156(5):893-906. doi: 10.1016/j.cell.2013.12.043. PMID:24581491 doi:http://dx.doi.org/10.1016/j.cell.2013.12.043
- ↑ Dardenne E, Polay Espinoza M, Fattet L, Germann S, Lambert MP, Neil H, Zonta E, Mortada H, Gratadou L, Deygas M, Chakrama FZ, Samaan S, Desmet FO, Tranchevent LC, Dutertre M, Rimokh R, Bourgeois CF, Auboeuf D. RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep. 2014 Jun 26;7(6):1900-13. doi: 10.1016/j.celrep.2014.05.010. Epub 2014 , Jun 6. PMID:24910439 doi:http://dx.doi.org/10.1016/j.celrep.2014.05.010
- ↑ Moy RH, Cole BS, Yasunaga A, Gold B, Shankarling G, Varble A, Molleston JM, tenOever BR, Lynch KW, Cherry S. Stem-loop recognition by DDX17 facilitates miRNA processing and antiviral defense. Cell. 2014 Aug 14;158(4):764-777. doi: 10.1016/j.cell.2014.06.023. PMID:25126784 doi:http://dx.doi.org/10.1016/j.cell.2014.06.023
- ↑ Yang J, Zhao Y, Kalita M, Li X, Jamaluddin M, Tian B, Edeh CB, Wiktorowicz JE, Kudlicki A, Brasier AR. Systematic Determination of Human Cyclin Dependent Kinase (CDK)-9 Interactome Identifies Novel Functions in RNA Splicing Mediated by the DEAD Box (DDX)-5/17 RNA Helicases. Mol Cell Proteomics. 2015 Oct;14(10):2701-21. doi: 10.1074/mcp.M115.049221. Epub , 2015 Jul 24. PMID:26209609 doi:http://dx.doi.org/10.1074/mcp.M115.049221
- ↑ Connerty P, Bajan S, Remenyi J, Fuller-Pace FV, Hutvagner G. The miRNA biogenesis factors, p72/DDX17 and KHSRP regulate the protein level of Ago2 in human cells. Biochim Biophys Acta. 2016 Oct;1859(10):1299-305. doi:, 10.1016/j.bbagrm.2016.07.013. Epub 2016 Jul 28. PMID:27478153 doi:http://dx.doi.org/10.1016/j.bbagrm.2016.07.013
- ↑ Ngo TD, Partin AC, Nam Y. RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis. Cell Rep. 2019 Dec 17;29(12):4024-4035.e5. doi: 10.1016/j.celrep.2019.11.059. PMID:31851931 doi:http://dx.doi.org/10.1016/j.celrep.2019.11.059
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