Cancer Res Treat.  2004 Aug;36(4):214-221.

DNA Damage Response Mediated through BRCA1

• Jang ER
• Lee JS

Abstract

The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast and ovarian cancer syndromes in women. The tumor suppressor, BRCA1 is known as a major player in the DNA damage response. These are evident from its loss, which causes malignant transformation in breast and ovary, and renders cells to become sensitive to a wide variety of DNA damaging agents. Here, we have implications on functional coupling of the pleiotropic roles of BRCA1, including DNA damage signal networking, DNA repair, transcription, and checkpoint of cell cycle, to tumor suppression by examining the molecular mechanisms and functions of BRCA1. The breast cancer susceptibility 1 (BRCA1) gene was identified and mapped to chromosome 17q21 by analyzing families at high risk from breast and ovarian cancer, and was first cloned in 1994 (1). The BRCA1 gene encodes a large nuclear protein that is ubiquitously expressed in a number of tissues. BRCA1 shares little structural resemblance to the majority of other known proteins (Fig. 1). Its ortholog is only found in mammals but not in yeast, fly, worm, or zebra fish, indicating that BRCA1 may come later in evolution and it may have more specialized and tissue-specific functions in mammalian cells. Although a number of studies delineating and deciphering the real biological roles of BRCA1 have accumulated, understanding these BRCA1 unique features still remains to be challengingly elucidated.

MeSH Terms

Breast
Breast Neoplasms
Cell Cycle
Clone Cells
Diptera
DNA Damage*
DNA Repair
DNA*
Female
Genes, BRCA1
Humans
Mammals
Nuclear Proteins
Ovarian Neoplasms
Ovary
Yeasts
Zebrafish
DNA
Nuclear Proteins

Figure

• 

  Fig. 1 A schematic diagram of the BRCA1 polypeptide and its interaction with different proteins. BRCA1 polypeptide has the phosphorylation sites (Ⓟ) shown as the seine residues that are phosphorylated and the kinases responsible. The proteins that are interact with BRCA1 are described below the interacting regions in BRCA1. Centrosome proteins, proteins belonging to BASC, and other BRCA2 interacting proteins have been shown to interact with BRCA1 in vivo. The BRCA1 polypeptide has N-terminal RING motif (red), nuclear localization signal (NLS, orange), and two C-terminal BRCT-domains (blue).

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  Fig. 2 Interactions of BRCA1 with a diversity of proteins and its possible roles. The putative cellular functions of protein- protein interactions of BRCA1 are shown in boxes. Their biological significances are not yet clarified.

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  Fig. 3 Hypothetical breast cancer development models based on previously reported genetic and biochemical data. The plausible roadmaps to breast cancers of (A) BRCA1- associated familial and (B) sporadic cases. (A) In familial breast cancer, one additional somatic mutation in the BRCA1 locus (LOH, loss of heterozygosity) in carriers of one germiline mutant BRCA1 allele (BRCA1+/-) results in a complete loss of BRCA1 function (BRCA1-/-). The BRCA1 deficiency (BRCA1-/-), in turn, causes genomic instability. DNA damage triggered by BRCA1 deficiency-induced genomic instability in BRCA1 null (BRCA1-/-) cells can either activate p53-dependent pathways (downward arrow; leading to cell cycle checkpoint, growth arrest, apoptosis, or senescence) or facilitate further mutations of additional breast cancer-associated susceptibility genes (p53, STK11, PTEN, EGFR, Her2 etc), and other tumor suppressor and oncogenes (rightward arrows, leading to carcinogenesis). Genomic instability for survival/growth advantages can be preferred in breast and ovary tissues, while p53 activation for growth arrest/death can be preferred in other tissues. (B) In sporadic breast cancer, the loss or reduction of BRCA1 expression is not necessary for cancer development. Otherwise, carcinogenesis events can be initiated by activation of oncogenes or inactivation of tumor suppressor genes, but not by somatic mutations or silencing BRCA1 (rare but theoretically possible). At least four somatic mutations are required for the development of sporadic breast cancers.

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  Fig. 4 The roles of BRCA1 in DNA damage responses. DNA damage triggers kinases-dependent phosphorylation of BRCA1. BRCA1 can process and integrate DNA damage signal by combination of its phosphorylation sites and extent, and BRCA1 transduces the processed signal to other DNA damage responses (arrow). The diverse functions of BRCA1 and other effectors (cell cycle checkpoint, DNA repair, transcription, and apoptosis), in turn, are regulated and tuned by the processed signal i.e. phosphorylation status of BRCA1. Therefore, BRCA1 might function as not only a signal processor but also a coordinator of various activities in DNA damage responses in order to maintain genome integrity.

Reference

1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266:66–71. PMID: 7545954.

2. Neuhausen SL, Marshall CJ. Loss of heterozygosity in familial tumors from three BRCA1-linked kindreds. Cancer Res. 1994; 54:6069–6072. PMID: 7954448.

3. Kinzler KW, Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature. 1997; 386:761–763. PMID: 9126728.

4. Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999; 3:389–395. PMID: 10198641.

5. Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27:247–254. PMID: 11242102.

6. Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan XY, Ried T, Deng CX. A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene. 1998; 17:3115–3124. PMID: 9872327.

7. Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997; 88:265–275. PMID: 9008167.

8. Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science. 1999; 285:747–750. PMID: 10426999.

9. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000; 14:927–939. PMID: 10783165.

10. Le Page F, Randrianarison V, Marot D, Cabannes J, Perricaudet M, Feunteun J, Sarasin A. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 2000; 60:5548–5552. PMID: 11034101.

11. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell. 1997; 90:425–435. PMID: 9267023.

12. Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000; 10:886–895. PMID: 10959836.

13. Zhong Q, Boyer TG, Chen PL, Lee WH. Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer Res. 2002; 62:3966–3970. PMID: 12124328.

14. Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, Livingston DM. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002; 111:393–405. PMID: 12419249.

15. Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature. 1997; 389:187–190. PMID: 9296497.

16. Williamson EA, Dadmanesh F, Koeffler HP. BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kip1). Oncogene. 2002; 21:3199–3206. PMID: 12082635.

17. Deng CX, Brodie SG. Roles of BRCA1 and its interacting proteins. Bioessays. 2000; 22:728–737. PMID: 10918303.

18. Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem. 1998; 273:25388–25392. PMID: 9738006.

19. Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999; 284:1354–1356. PMID: 10334989.

20. Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nat Genet. 1997; 16:298–302. PMID: 9207798.

21. Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet. 1999; 22:37–43. PMID: 10319859.

22. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science. 1999; 286:1162–1166. PMID: 10550055.

23. Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000; 404:201–204. PMID: 10724175.

24. Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F. Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol. 2004; 24:708–718. PMID: 14701743.

25. Starita LM, Parvin JD. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Curr Opin Cell Biol. 2003; 15:345–350. PMID: 12787778.

26. Kleiman FE, Manley JL. The BARD1-CstF-50 interaction links mRNA 3 end formation to DNA damage and tumor suppression. Cell. 2001; 104:743–753. PMID: 11257228.

27. Bianco T, Chenevix-Trench G, Walsh DC, Cooper JE, Dobrovic A. Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis. 2000; 21:147–151. PMID: 10657950.