Microcephalin Regulates BRCA2 and Rad51-associated DNA Double-strand Break Repair

Overview

Journal Cancer Res

Specialty Oncology

Date 2009 Jun 25

PMID 19549900

Citations 31

Authors

Xianglin Wu

Gourish Mondal

Xianshu Wang

Jianmin Wu

Lin Yang

Vernon S Pankratz

Matthew Rowley

Fergus J Couch

Affiliations

Soon will be listed here.

Abstract

Microcephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (gammaH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH(2) terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks.

Citing Articles

Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function.

He H, Wang Y, Tang B, Dong Q, Wu C, Sun W Nat Aging. 2024; 4(4):510-526.

PMID: 38632351 DOI: 10.1038/s43587-024-00609-z.

DNA damage and repair: underlying mechanisms leading to microcephaly.

Ribeiro J, Altinisik N, Rajan N, Verslegers M, Baatout S, Gopalakrishnan J Front Cell Dev Biol. 2023; 11:1268565.

PMID: 37881689 PMC: 10597653. DOI: 10.3389/fcell.2023.1268565.

Mutation Profile via Next-Generation Sequencing in Patients with Colorectal Adenocarcinoma and Its Clinicopathological Correlation.

Osman S, Kahraman Cetin N, Erdogdu I, Meteoglu I Turk J Gastroenterol. 2023; 34(11):1124-1133.

PMID: 37737217 PMC: 10724784. DOI: 10.5152/tjg.2023.22682.

The emerging role of MCPH1/BRIT1 in carcinogenesis.

Alsolami M, Aboalola D, Malibari D, Alghamdi T, Alshekhi W, Jad H Front Oncol. 2023; 13:1047588.

PMID: 36845691 PMC: 9951231. DOI: 10.3389/fonc.2023.1047588.

Multifaceted Microcephaly-Related Gene MCPH1.

Kristofova M, Ori A, Wang Z Cells. 2022; 11(2).

PMID: 35053391 PMC: 8774270. DOI: 10.3390/cells11020275.

References

Yu X, Chini C, He M, Mer G, Chen J . The BRCT domain is a phospho-protein binding domain. Science. 2003; 302(5645):639-42. DOI: 10.1126/science.1088753. View

Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N . Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006; 22(6):719-729. DOI: 10.1016/j.molcel.2006.05.022. View

Wood J, Singh N, Mer G, Chen J . MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. J Biol Chem. 2007; 282(48):35416-23. PMC: 2128040. DOI: 10.1074/jbc.M705245200. View

Pierce A, Johnson R, Thompson L, Jasin M . XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 1999; 13(20):2633-8. PMC: 317094. DOI: 10.1101/gad.13.20.2633. View

Lin S, Rai R, Li K, Xu Z, Elledge S . BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proc Natl Acad Sci U S A. 2005; 102(42):15105-9. PMC: 1257745. DOI: 10.1073/pnas.0507722102. View

Wu K, Hinson S, Ohashi A, Farrugia D, Wendt P, Tavtigian S . Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res. 2005; 65(2):417-26. View

Jackson A, Eastwood H, Bell S, Adu J, Toomes C, Carr I . Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002; 71(1):136-42. PMC: 419993. DOI: 10.1086/341283. View

Lingle W, Barrett S, Negron V, DAssoro A, Boeneman K, Liu W . Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A. 2002; 99(4):1978-83. PMC: 122305. DOI: 10.1073/pnas.032479999. View

Neitzel H, Neumann L, Schindler D, Wirges A, Tonnies H, Trimborn M . Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition. Am J Hum Genet. 2002; 70(4):1015-22. PMC: 379095. DOI: 10.1086/339518. View

10.

Varon R, Vissinga C, Platzer M, Cerosaletti K, Chrzanowska K, Saar K . Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998; 93(3):467-76. DOI: 10.1016/s0092-8674(00)81174-5. View

11.

Xu X, Lee J, Stern D . Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004; 279(33):34091-4. DOI: 10.1074/jbc.C400139200. View

12.

Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M . Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 1998; 62(3):551-61. PMC: 1376949. DOI: 10.1086/301755. View

13.

Koonin E, Altschul S, Bork P . BRCA1 protein products ... Functional motifs. Nat Genet. 1996; 13(3):266-8. DOI: 10.1038/ng0796-266. View

14.

Ohashi A, Zdzienicka M, Chen J, Couch F . Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem. 2005; 280(15):14877-83. DOI: 10.1074/jbc.M414669200. View

15.

Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park S . SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008; 135(5):907-18. PMC: 2853975. DOI: 10.1016/j.cell.2008.10.025. View

16.

Wang R, Sengupta K, Li C, Kim H, Cao L, Xiao C . Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008; 14(4):312-23. PMC: 2643030. DOI: 10.1016/j.ccr.2008.09.001. View

17.

Plo I, Laulier C, Gauthier L, Lebrun F, Calvo F, Lopez B . AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51. Cancer Res. 2008; 68(22):9404-12. DOI: 10.1158/0008-5472.CAN-08-0861. View

18.

Jeffers L, Coull B, Stack S, Morrison C . Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization. Oncogene. 2007; 27(1):139-44. DOI: 10.1038/sj.onc.1210595. View

19.

Rai R, Dai H, Multani A, Li K, Chin K, Gray J . BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell. 2006; 10(2):145-57. PMC: 1557410. DOI: 10.1016/j.ccr.2006.07.002. View

20.

Moynahan M, Pierce A, Jasin M . BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001; 7(2):263-72. DOI: 10.1016/s1097-2765(01)00174-5. View