| Structural highlights
Disease
[CTIP_HUMAN] Seckel syndrome;Jawad syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986).[1] [2]
Function
[CTIP_HUMAN] Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double-strand break (DSB) repair through the homologous recombination (HR) pathway. HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse. Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ). Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:10764811, PubMed:10910365, PubMed:15485915, PubMed:16581787, PubMed:16818604, PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:20829486). During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations (By similarity).[UniProtKB:Q80YR6][3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Mammalian CtIP protein has major roles in DNA double-strand break (DSB) repair. Although it is well established that CtIP promotes DNA-end resection in preparation for homology-dependent DSB repair, the molecular basis for this function has remained unknown. Here we show by biophysical and X-ray crystallographic analyses that the N-terminal domain of human CtIP exists as a stable homotetramer. Tetramerization results from interlocking interactions between the N-terminal extensions of CtIP's coiled-coil region, which lead to a 'dimer-of-dimers' architecture. Through interrogation of the CtIP structure, we identify a point mutation that abolishes tetramerization of the N-terminal domain while preserving dimerization in vitro. Notably, we establish that this mutation abrogates CtIP oligomer assembly in cells, thus leading to strong defects in DNA-end resection and gene conversion. These findings indicate that the CtIP tetramer architecture described here is essential for effective DSB repair by homologous recombination.
CtIP tetramer assembly is required for DNA-end resection and repair.,Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L Nat Struct Mol Biol. 2015 Jan 5. doi: 10.1038/nsmb.2937. PMID:25558984[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wu M, Soler DR, Abba MC, Nunez MI, Baer R, Hatzis C, Llombart-Cussac A, Llombart-Bosch A, Aldaz CM. CtIP silencing as a novel mechanism of tamoxifen resistance in breast cancer. Mol Cancer Res. 2007 Dec;5(12):1285-95. doi: 10.1158/1541-7786.MCR-07-0126. PMID:18171986 doi:http://dx.doi.org/10.1158/1541-7786.MCR-07-0126
- ↑ Rebbeck TR, Mitra N, Domchek SM, Wan F, Friebel TM, Tran TV, Singer CF, Tea MK, Blum JL, Tung N, Olopade OI, Weitzel JN, Lynch HT, Snyder CL, Garber JE, Antoniou AC, Peock S, Evans DG, Paterson J, Kennedy MJ, Donaldson A, Dorkins H, Easton DF, Rubinstein WS, Daly MB, Isaacs C, Nevanlinna H, Couch FJ, Andrulis IL, Freidman E, Laitman Y, Ganz PA, Tomlinson GE, Neuhausen SL, Narod SA, Phelan CM, Greenberg R, Nathanson KL. Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes. Cancer Res. 2011 Sep 1;71(17):5792-805. doi: 10.1158/0008-5472.CAN-11-0773. Epub , 2011 Jul 28. PMID:21799032 doi:http://dx.doi.org/10.1158/0008-5472.CAN-11-0773
- ↑ Yu X, Baer R. Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J Biol Chem. 2000 Jun 16;275(24):18541-9. PMID:10764811 doi:10.1074/jbc.M909494199
- ↑ Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, Lee EY, Lee WH. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature. 2000 Jul 13;406(6792):210-5. PMID:10910365 doi:10.1038/35018134
- ↑ Yu X, Chen J. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol. 2004 Nov;24(21):9478-86. PMID:15485915 doi:10.1128/MCB.24.21.9478-9486.2004
- ↑ Liu F, Lee WH. CtIP activates its own and cyclin D1 promoters via the E2F/RB pathway during G1/S progression. Mol Cell Biol. 2006 Apr;26(8):3124-34. PMID:16581787 doi:10.1128/MCB.26.8.3124-3134.2006
- ↑ Yu X, Fu S, Lai M, Baer R, Chen J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 2006 Jul 1;20(13):1721-6. PMID:16818604 doi:10.1101/gad.1431006
- ↑ Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP. Human CtIP promotes DNA end resection. Nature. 2007 Nov 22;450(7169):509-14. Epub 2007 Oct 28. PMID:17965729 doi:10.1038/nature06337
- ↑ Huertas P, Jackson SP. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem. 2009 Apr 3;284(14):9558-65. doi: 10.1074/jbc.M808906200. Epub 2009, Feb 7. PMID:19202191 doi:10.1074/jbc.M808906200
- ↑ Yuan J, Chen J. N terminus of CtIP is critical for homologous recombination-mediated double-strand break repair. J Biol Chem. 2009 Nov 13;284(46):31746-52. doi: 10.1074/jbc.M109.023424. Epub, 2009 Sep 16. PMID:19759395 doi:10.1074/jbc.M109.023424
- ↑ You Z, Shi LZ, Zhu Q, Wu P, Zhang YW, Basilio A, Tonnu N, Verma IM, Berns MW, Hunter T. CtIP links DNA double-strand break sensing to resection. Mol Cell. 2009 Dec 25;36(6):954-69. doi: 10.1016/j.molcel.2009.12.002. PMID:20064462 doi:10.1016/j.molcel.2009.12.002
- ↑ Kaidi A, Weinert BT, Choudhary C, Jackson SP. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science. 2010 Sep 10;329(5997):1348-53. doi: 10.1126/science.1192049. PMID:20829486 doi:10.1126/science.1192049
- ↑ Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L. CtIP tetramer assembly is required for DNA-end resection and repair. Nat Struct Mol Biol. 2015 Jan 5. doi: 10.1038/nsmb.2937. PMID:25558984 doi:http://dx.doi.org/10.1038/nsmb.2937
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