| Structural highlights
Function
CCAR2_HUMAN Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions (PubMed:22446626). Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis (PubMed:18235501, PubMed:18235502, PubMed:23352644). Inhibits SUV39H1 methyltransferase activity (PubMed:19218236). Mediates ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:19131338). Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress (PubMed:23398316). Regulates the circadian expression of the core clock components NR1D1 and BMAL1 (PubMed:23398316). Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation (PubMed:23398316). Represses the ligand-dependent transcriptional activation function of ESR2 (PubMed:20074560). Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1 (PubMed:24415752). Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization (PubMed:21030595). Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway (PubMed:24824780). Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3 (PubMed:25661920). Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2 (PubMed:25732823). Represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro (PubMed:25361978).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
References
- ↑ Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature. 2008 Jan 31;451(7178):583-6. PMID:18235501 doi:10.1038/nature06500
- ↑ Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature. 2008 Jan 31;451(7178):587-90. PMID:18235502 doi:10.1038/nature06515
- ↑ Garapaty S, Xu CF, Trojer P, Mahajan MA, Neubert TA, Samuels HH. Identification and characterization of a novel nuclear protein complex involved in nuclear hormone receptor-mediated gene regulation. J Biol Chem. 2009 Mar 20;284(12):7542-52. PMID:19131338 doi:10.1074/jbc.M805872200
- ↑ Li Z, Chen L, Kabra N, Wang C, Fang J, Chen J. Inhibition of SUV39H1 methyltransferase activity by DBC1. J Biol Chem. 2009 Apr 17;284(16):10361-6. PMID:19218236 doi:10.1074/jbc.M900956200
- ↑ Koyama S, Wada-Hiraike O, Nakagawa S, Tanikawa M, Hiraike H, Miyamoto Y, Sone K, Oda K, Fukuhara H, Nakagawa K, Kato S, Yano T, Taketani Y. Repression of estrogen receptor beta function by putative tumor suppressor DBC1. Biochem Biophys Res Commun. 2010 Feb 12;392(3):357-62. PMID:20074560 doi:10.1016/j.bbrc.2010.01.025
- ↑ Hiraike H, Wada-Hiraike O, Nakagawa S, Koyama S, Miyamoto Y, Sone K, Tanikawa M, Tsuruga T, Nagasaka K, Matsumoto Y, Oda K, Shoji K, Fukuhara H, Saji S, Nakagawa K, Kato S, Yano T, Taketani Y. Identification of DBC1 as a transcriptional repressor for BRCA1. Br J Cancer. 2010 Mar 16;102(6):1061-7. PMID:20160719 doi:10.1038/sj.bjc.6605577
- ↑ Chini CC, Escande C, Nin V, Chini EN. HDAC3 is negatively regulated by the nuclear protein DBC1. J Biol Chem. 2010 Dec 24;285(52):40830-7. PMID:21030595 doi:10.1074/jbc.M110.153270
- ↑ Close P, East P, Dirac-Svejstrup AB, Hartmann H, Heron M, Maslen S, Chariot A, Söding J, Skehel M, Svejstrup JQ. DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature. 2012 Mar 25;484(7394):386-9. PMID:22446626 doi:10.1038/nature10925
- ↑ Kim W, Kim JE. Deleted in breast cancer 1 (DBC1) deficiency results in apoptosis of breast cancer cells through impaired responses to UV-induced DNA damage. Cancer Lett. 2013 Jun 10;333(2):180-6. PMID:23352644 doi:10.1016/j.canlet.2013.01.026
- ↑ Chini CC, Escande C, Nin V, Chini EN. DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα. Biochem J. 2013 May 1;451(3):453-61. PMID:23398316 doi:10.1042/BJ20121085
- ↑ Nin V, Chini CC, Escande C, Capellini V, Chini EN. Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis. J Biol Chem. 2014 Feb 28;289(9):5518-27. PMID:24415752 doi:10.1074/jbc.M113.512913
- ↑ Pangon L, Mladenova D, Watkins L, Van Kralingen C, Currey N, Al-Sohaily S, Lecine P, Borg JP, Kohonen-Corish MR. MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm. Int J Cancer. 2015 Jan 1;136(1):55-64. doi: 10.1002/ijc.28967. Epub 2014 May 27. PMID:24824780 doi:https://dx.doi.org/10.1002/ijc.28967
- ↑ Magni M, Ruscica V, Buscemi G, Kim JE, Nachimuthu BT, Fontanella E, Delia D, Zannini L. Chk2 and REGgamma-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res. 2014 Dec 1;42(21):13150-60. doi: 10.1093/nar/gku1065. Epub, 2014 Oct 31. PMID:25361978 doi:https://dx.doi.org/10.1093/nar/gku1065
- ↑ Sakurabashi A, Wada-Hiraike O, Hirano M, Fu H, Isono W, Fukuda T, Morita Y, Tanikawa M, Miyamoto Y, Oda K, Kawana K, Osuga Y, Fujii T. CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase. J Steroid Biochem Mol Biol. 2015 May;149:80-8. PMID:25661920 doi:10.1016/j.jsbmb.2015.02.001
- ↑ Qin B, Minter-Dykhouse K, Yu J, Zhang J, Liu T, Zhang H, Lee S, Kim J, Wang L, Lou Z. DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep. 2015 Mar 3;10(8):1324-34. PMID:25732823 doi:10.1016/j.celrep.2015.01.066
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