Brca1 and brca2: Role in the DNA damage response, cancer formation and treatment

The DNA Damage Response: Implications on Cancer Formation and Treatment

Volumn , Issue , 2009, Pages 415-443

  Savage, Kienan ^a   Harkin, D Paul ^a  

^a QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 83755165693     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-90-481-2561-6_18     Document Type: Chapter

References (183)

1. Hall, J. M., Lee, M. K., and Newmann, B., Linkage of early-onset breast cancer to chromosome 17q21. Science 250, 1684 (1990).
2. Futreal, P. A. et al., BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182), 120 (1994).
3. Miki, Y. et al., A strong candidate for the breast cancer susceptibility gene BRCA1. Science 266, 66 (1994).
4. Wooster, R. et al., Identification of the breast cancer susceptibility gene, BRCA2. Nature 378, 789 (1995)
5. Wooster, R. et al., Localisation of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265, 2088 (1994).
6. Ford, D. et al., Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3), 676 (1998).
7. Risch, H. A. et al., Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68 (3), 700 (2001).
8. Welcsh, P. L. and King, M. C., BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 10 (7), 705 (2001).
9. Esteller, Manel et al., Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92 (7), 564 (2000).
10. Blackwood, M. A. and Weber, B. L., BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 16 (5), 1969 (1998)
11. Tan, D. S. P., Marchio, C., and Reis-Filho, J. S., Hereditary breast cancer: from molecular pathology to tailored therapies. J Clin Pathol 61 (10), 1073 (2008).
12. Paterson, J. W., BRCA1: a review of structure and putative functions. Dis Markers 13 (4), 261 (1998).
13. Hashizume, R. et al., The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276 (18), 14537 (2001).
14. Ruffner, H. et al., Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA 98, 5134 (2001).
15. Brzovic, P. S., Meza, J. E., King, M. -C., and Klevit, R. E., BRCA1 RING domain cancerpredisposing mutations: structural consequences and effects on protein-protein interactions. J Biol Chem 8, 833 (2001).
16. Irminger-Finger, I. and Jefford, C. E., Is there more to BARD1 than BRCA1? Nat Rev Cancer 6 (5), 382 (2006)
17. Sauer, M. K. and Andrulis, I. L., Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. J Med Genet 42 (8), 633 (2005)
18. Thai, T. H. et al., Mutations in the BRCA1- associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet 7 (2), 195 (1998).
19. Chapman, M. S. and Verma, I. M., Transcriptional activation by BRCA1. Nature 382 (6593), 678 (1996).
20. Hu, Y. -F., Miyake, T., Ye, Q., and Li, R., Characterization of a novel trans -activation domain of BRCA1 that functions in concert with the BRCA1 C-terminal (BRCT) domain. J Biol Chem 275, 40910 (2000).
21. Monteiro, A. N., August, A., and Hanafusa, H., Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc Natl Acad Sci USA 93 (24), 13595 (1996).
22. Yu, Xiaochun et al., The BRCT domain is a phospho-protein binding domain. Science 302 (5645), 639 (2003)
23. Manke, I. A., Lowery, D. M., Nguyen, A., and Yaffe, M. B., BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302 (5645), 636 (2003).
24. Monteiro, A. N. A., August, A., and Hanafusa, H., Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc Natl Acad Sci USA 93, 13595 (1996)
25. Williams, R. S. and Glover, J. N. M., Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem 278, 2630 (2002).
26. Chen, C. -F. et al., The nuclear localisation sequences of the BRCA1 protein interact with the importin-? subunit of the nuclear transport signal. J Biol Chem 271 (51), 32863 (1996)
27. Thakur, S. et al., Localisation of BRCA1 and a splice variant identifies the nuclear localisation signal. Mol Cell Biol 17, 444 (1997).
28. Rodriguez, J. A. and Henderson, B. R., Identification of a functional nuclear export sequence in BRCA1. J Biol Chem 275 (49), 38589 (2000).
29. Scully, R. et al., Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88 (2), 265 (1997)
30. Scully, R. et al., Location of BRCA1 in human breast and ovarian cancer cells. Science 272, 123 (1996).
31. Scully, R. et al., Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell 4 (6), 1093 (1999).
32. Moynahan, M. E., Chiu, J. W., Koller, B. H., and Jasin, M., Brca1 controls homology-directed DNA repair. Mol Cell 4 (4), 511 (1999)
33. Snouwaert, J. N. et al., BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. Oncogene 18 (55), 7900 (1999).
34. Bhattacharyya, A. et al., The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275 (31), 23899 (2000)
35. Zhou, C., Huang, P., and Liu, J., The carboxyl-terminal of BRCA1 is required for subnuclear assembly of RAD51 after treatment with cisplatin but not ionizing radiation in human breast and ovarian cancer cells. Biochem Biophys Res Commun 336 (3), 952 (2005).
36. Lee, J. S. et al., hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404 (6774), 201 (2000)
37. Zhang, J. et al., Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol 24 (2), 708 (2004).
38. Zhong, Q., Chen, C. -F., Chen, P. -L., and Lee, W. -H., BRCA1 Facilitates microhomologymediated end joining of DNA double strand breaks. J Biol Chem 277 (32), 28641 (2002).
39. Wang, Y. et al., BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14 (8), 927 (2000).
40. Wood, R. D., Nucleotide excision repair in mammalian cells. J Biol Chem 272 (38), 23465 (1997).
41. Le Page, F. et al., BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res 60 (19), 5548 (2000).
42. Kleiman, F. E. et al., BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II. Genes Dev 19 (10), 1227 (2005)
43. Starita, L. M. et al., BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J Biol Chem 280 (26), 24498 (2005).
44. Hartman, A. -R. and Ford, J. M., BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet 32, 180 (2002).
45. Chen, Y. et al., BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res 56 (14), 3168 (1996)
46. Thomas, J. E. et al., Subcellular localisation and analysis of apparent 180-kDa and 220-kDa proteins of the breast cancer susceptibility gene, BRCA1. J Biol Chem 271 (45), 28630 (1996).
47. Scully, R. et al., Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90 (3), 425 (1997)
48. Thomas, J. E. et al., Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage. Cell Growth Differ 8 (7), 801 (1997).
49. Gatei, M. et al., Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 60 (12), 3299 (2000)
50. Tibbetts, R. S. et al., Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 14 (23), 2989 (2000).
51. Gatei, M. et al., Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. J Biol Chem 276 (20), 17276 (2001).
52. Zhong, Q. et al., Association of BRCA1 with the hRAd50-hMre11-p95 complex and the DNA damage response. Science 285, 747 (1999).
53. Xu, B., Kim, St., and Kastan, M. B., Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 21 (10), 3445 (2001).
54. Xu, X. et al., Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3, 389 (1999).
55. Tomlinson, G. E. et al., Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. Cancer Res 58 (15), 3237 (1998).
56. Fabbro, M. et al., BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J Biol Chem 279 (30), 31251 (2004).
57. Foray, N. et al., A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Embo J 22 (11), 2860 (2003).
58. Li, Shang et al., Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem 274 (16), 11334 (1999).
59. Yarden, R. I. et al., BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 30 (3), 285 (2002).
60. Xu, B., O'Donnell, A. H., Kim, S. -T., and Kastan, M. B., Phosphorylation of serine 1387 in Brca1 is specifically required for the ATM-mediated S-phase checkpoint after ionizing irradiation. Cancer Res 62, 4588 (2002).
61. Kim, S. -T., Xu, B., and Kastan, M. B., Involvement of the cohesin protein, Smc1, in ATMdependent and independent responses to DNA damage. Genes Dev 16 (5), 560 (2002)
62. Kitagawa, R., Bakkenist, C. J., McKinnon, P. J., and Kastan, M. B., Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev 18 (12), 1423 (2004)
63. Yazdi, P. T. et al., SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev 16 (5), 571 (2002).
64. Somasundaram, K. et al., Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CIP1. Nature 389, 187 (1997).
65. MacLachlan, T. K. et al., BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. J Biol Chem 275 (4), 2777 (1999)
66. Mullan, P. B. et al., BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. Oncogene 20, 6123 (2001)
67. Williamson, E. A., Dadmanesh, F., and Koeffler, H. P., BRCA1 transactivates the cyclin-dependent kinase inhibitor p27Kip1. Oncogene 21, 3199 (2002).
68. MacLachlan, T. K. et al., BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. J Biol Chem 275 (4), 2777 (2000)
69. Ree, A. H. et al., Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1. Oncogene 22 (55), 8952 (2003).
70. Greenberg, R. A. et al., Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev 20 (1), 34 (2006).
71. Chiba, N. and Parvin, J. D., Redistribution of BRCA1 among four different protein complexes following replication blockage. J Biol Chem 276 (42), 38549 (2001).
72. Kim, H., Chen, J., and Yu, X., Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316 (5828), 1202 (2007)
73. Sobhian, B. et al., RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316 (5828), 1198 (2007)
74. Wang, B. et al., Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316 (5828), 1194 (2007).
75. Huen, M. S. et al., RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131 (5), 901 (2007)
76. Kolas, N. K. et al., Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318 (5856), 1637 (2007)
77. Mailand, N. et al., RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131 (5), 887 (2007)
78. Wang, B. and Elledge, S. J., Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. PNAS 104 (52), 20759 (2007).
79. Kennedy, R. D. and D'Andrea, A. D., The Fanconi anemia/BRCA pathway: new faces in the crowd. Genes Dev 19 (24), 2925 (2005).
80. Meetei, A. R. et al., A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet 35 (2), 165 (2003).
81. Wang, X., Andreassen, P. R., and D'Andrea, A. D., Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 24 (13), 5850 (2004).
82. Howlett, N. G. et al., Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297 (5581), 606 (2002).
83. Andreassen, P. R., D'Andrea, A. D., and Taniguchi, T., ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18 (16), 1958 (2004)
84. Wang, X. et al., Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol 27 (8), 3098 (2007).
85. Andreassen, P. R., Ho, G. P. H., and D'Andrea, A. D., DNA damage responses and their many interactions with the replication fork. Carcinogenesis 27 (5), 883 (2006).
86. Garcia-Higuera, I. et al., Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7 (2), 249 (2001).
87. Taniguchi, T. et al., S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 100 (7), 2414 (2002).
88. Nakanishi, K. et al., Interaction of FANCD2 and NBS1 in the DNA damage response. Nat Cell Biol 4 (12), 913 (2002).
89. May, K. M. and Hardwick, K. G., The spindle checkpoint. J Cell Sci 119 (20), 4139 (2006).
90. Lafarge, S., Sylvain, V., Ferrara, M., and Bignon, Y. J., Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 20 (45), 6597 (2001)
91. Tassone, P. et al., BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 88 (8), 1285 (2003).
92. Quinn, J. E. et al., BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res 63 (19), 6221 (2003).
93. Bae, I. et al., BRCA1 regulates gene expression for orderly mitotic progression. Cell Cycle 4 (11), 1641 (2005)
94. Wang, R. -H., Yu, H., and Deng, C. -X., A requirement for breast-cancerassociated gene 1 (BRCA1) in the spindle checkpoint. PNAS 101 (49), 17108 (2004).
95. Lorick, K. L. et al., RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci USA 96, 11354 (1999).
96. Brzovic, P. S. et al., Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. PNAS 100 (10), 5646 (2003).
97. Meetei, A. R., Yan, Z., andWang, W., FANCL replaces BRCA1 as the likely ubiquitin ligase responsible for FANCD2 monoubiquitination. Cell Cycle 3 (2), 179 (2004).
98. Vandenberg, C. J. et al., BRCA1-independent ubiquitination of FANCD2. Mol Cell 12 (1), 247 (2003).
99. Taniguchi, T. et al., S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 100 (7), 2414 (2002)
100. Taniguchi, T. et al., Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109 (4), 459 (2002)
101. Taniguchi, T. et al., Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 9 (5), 568 (2003).
102. Mallery, D. L., Vandenberg, C. J., and Hiom, K., Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. Embo J 21 (24), 6755 (2002).
103. Morris, J. R. and Solomon, E., BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet 13 (8), 807 (2004).
104. Wu-Baer, F., Lagrazon, K., Yuan, W., and Baer, R., The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem 278 (37), 34743 (2003).
105. Christensen, D. E., Brzovic, P. S., and Klevit, R. E., E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat Struct Mol Biol 14 (10), 941 (2007).
106. Lee, K. -B., Wang, D., Lippard, S. J., and Sharp, P. A., Transcription-coupled and DNA damage-dependent ubiquitination of RNA polymerase II in vitro. PNAS 99 (7), 4239 (2002).
107. Morris, J. R. et al., Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility. Hum Mol Genet 15 (4), 599 (2006).
108. Miki, Y. et al., A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182), 66 (1994).
109. Humphrey, J. S. et al., Human BRCA1 inhibits growth in yeast: potential use in diagnostic testing. PNAS 94 (11), 5820 (1997).
110. Anderson, S. F. et al., BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet 19 (3), 254 (1998)
111. Scully, R. et al., BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci USA 94, 5605 (1997).
112. MacLachlan, T. K., Takimoto, R., and El-Deiry, W. S., BRCA1 directs a selective p53- dependent transcriptional response towards growth arrest and DNA repair targets. Mol Cell Biol 22 (12), 4280 (2002).
113. Heldring, N. et al., Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87 (3), 905 (2007).
114. Fan, S. et al., Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene 20, 77 (2001)
115. Zheng, L. et al., BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci USA 98 (17), 9587 (2001).
116. Kawai, H. et al., Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene 21, 7730 (2002).
117. Aiyar, S. E. et al., Attenuation of estrogen receptor {alpha}-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes Dev 18 (17), 2134 (2004).
118. Paull, T. T. et al., From the cover: direct DNA binding by Brca1. PNAS 98 (11), 6086 (2001).
119. Hosey, A. M. et al., Molecular basis for estrogen receptor {alpha} deficiency in BRCA1- linked breast cancer. J Natl Cancer Inst 99 (22), 1683 (2007).
120. Chen, G. -C. et al., Rb-associated protein 46 (RbAp46) inhibits transcriptional transactivation mediated by BRCA1. Biochem Biophys Res Commun 284, 507 (2001)
121. Yarden, R. I. and Brody, L. C., BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci USA 96 (9), 4983 (1999).
122. Kadam, S. et al., Functional selectivity of recombinantmammalian SWI/SNF subunits. Genes Dev 14 (19), 2441 (2000).
123. Oishi, H. et al., An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification. J Biol Chem 281 (1), 20 (2006).
124. Fan, W. et al., BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. J Biol Chem 277, 8061 (2002).
125. Zhao, H. et al., Activation of the transcription factor Oct-1 in response to DNA damage. Cancer Res 60 (22), 6276 (2000).
126. Andrews, H. N. et al., BRCA1 regulates the interferon gamma -mediated apoptotic response. J Biol Chem 277 (29), 26225 (2002).
127. Li, S. et al., Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem 274, 11334 (1999)
128. Yu, X. et al., The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathways of transcriptional repression. J Biol Chem 273 (39), 25388 (1998).
129. Zheng, L. et al., Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell 6, 757 (2000).
130. Furuta, S. et al., Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. Cancer Cell 10 (1), 13 (2006).
131. Horwitz, A. A. et al., A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase. PNAS 104 (16), 6614 (2007).
132. Kennedy, R. D. et al., BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene. Cancer Res 65 (22), 10265 (2005)
133. Li, H., Lee, T. -H., and Avraham, H., A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J Biol Chem 277 (23), 20965 (2002).
134. Park, M. A., Seok, Y. -J., Jeong, G., and Lee, J. -S., SUMO1 negatively regulates BRCA1- mediated transcription, via modulation of promoter occupancy. Nucleic Acids Res 36 (1), 263 (2008).
135. Li, C. J. et al., Dynamic redistribution of calmodulin in HeLa cells during cell division as revealed by a GFP-calmodulin fusion protein technique. J Cell Sci 112 (Pt 10), 1567 (1999)
136. Li, X. et al., Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J Biol Chem 282 (50), 36177 (2007).
137. Ziv, Y. et al., Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 8 (8), 870 (2006).
138. Tavtigian, S. V. et al., The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12 (3), 333 (1996).
139. Bork, P., Blomberg, N., and Nilges, M., Internal repeats in the BRCA2 protein sequence. Nat Genet 13 (1), 22 (1996).
140. Bignell, G. et al., The BRC repeats are conserved in mammalian BRCA2 proteins. Hum Mol Genet 6 (1), 53 (1997).
141. Sharan, S. K. et al., Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804 (1997).
142. Wong, A. K. C. et al., RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J Biol Chem 272 (51), 31941 (1997).
143. Pellegrini, L. et al., Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420 (6913), 287 (2002).
144. Venkitaraman, A. R., Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci 114 (Pt 20), 3591 (2001).
145. Esashi, F. et al., CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434 (7033), 598 (2005).
146. Esashi, F. et al., Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat Struct Mol Biol 14 (6), 468 (2007).
147. Yang, H. et al., BRCA2 function in DNA binding and recombination from a BRCA2-DSS1- ssDNA structure. Science 297 (5588), 1837 (2002).
148. Bochkarev, A. and Bochkareva, E., From RPA to BRCA2: lessons from single-stranded DNA binding by the OB-fold. Curr Opin Struct Biol 14 (1), 36 (2004)
149. Richard, D. J. et al., Singlestranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 453 (7195), 677 (2008).
150. Marston, N. J. et al., Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals. Mol Cell Biol 19 (7), 4633 (1999).
151. Gudmundsdottir, K. et al., DSS1 is required for RAD51 focus formation and genomic stability in mammalian cells. EMBO Rep 5 (10), 989 (2004).
152. Connor, F. et al., Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet 17 (4), 423 (1997)
153. Yu, V. P. C. C. et al., Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev 14 (11), 1400 (2000).
154. Reid, S. et al., Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2), 162 (2007)
155. Xia, B. et al., Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39 (2), 159 (2007).
156. Erkko, H. et al., A recurrent mutation in PALB2 in Finnish cancer families. Nature 446 (7133), 316 (2007)
157. Potapova, A. et al., Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer Res 68 (4), 998 (2008)
158. Rahman, N. et al., PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2), 165 (2007)
159. Tischkowitz, M. et al., Analysis of PALB2/FANCN-associated breast cancer families. PNAS 104 (16), 6788 (2007).
160. Matsuoka, S. et al., ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316 (5828), 1160 (2007)
161. Patel, K. J. et al., Involvement of Brca2 in DNA repair. Mol Cell 1 (3), 347 (1998).
162. Futamura, M. et al., Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1. Cancer Res 60 (6), 1531 (2000).
163. Marmorstein, L. Y. et al., A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell 104 (2), 247 (2001).
164. Hughes-Davies, L. et al., EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115 (5), 523 (2003).
165. Shin, S. and Verma, I. M., BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. PNAS 100 (12), 7201 (2003).
166. Haber, D. A., The BRCA2-EMSY connection: implications for breast and ovarian tumorigenesis. Cell 115 (5), 507 (2003).
167. Land, C. E. et al., Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990. Radiat Res 160 (6), 707 (2003)
168. Land, C. E., Tokunaga, M., Tokuoka, S., and Nakamura, N., Early-onset breast cancer in A-bomb survivors. Lancet 342 (8865), 237 (1993).
169. Hu, Y. et al., Modulation of aromatase expression by BRCA1: a possible link to tissuespecific tumor suppression. Oncogene 24 (56), 8343 (2005)
170. Lu, M. et al., BRCA1 negatively regulates the cancer-associated aromatase promoters I. 3 and II in breast adipose fibroblasts and malignant epithelial cells. J Clin Endocrinol Metab 91 (11), 4514 (2006).
171. Ganesan, S. et al., Association of BRCA1 with the inactive X chromosome and XIST RNA. Philos Trans R Soc Lond B Biol Sci 359 (1441), 123 (2004)
172. Ganesan, S. et al., BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111 (3), 393 (2002).
173. Pageau, G. J., Hall, L. L., and Lawrence, J. B., BRCA1 does not paint the inactive X to localize XIST RNA but may contribute to broad changes in cancer that impact XIST and Xi heterochromatin. J Cell Biochem 100 (4), 835 (2007)
174. Xiao, C. et al., The XIST noncoding RNA functions independently of BRCA1 in X inactivation. Cell 128 (5), 977 (2007).
175. Chappuis, P. O. et al., A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39 (8), 608 (2002).
176. Delaloge, S. et al., BRCA1 germ-line mutation: predictive of sensitivity to anthracyclin alkylating agents regimens but not to taxanes? ASCO Meet Abstr 26 (15 Suppl), 574 (2008)
177. Goffin, J. R. et al., Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer 97 (3), 527 (2003)
178. Kirova, Y. M. et al., Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer 41 (15), 2304 (2005).
179. Quinn, J. E. et al., BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13 (24), 7413 (2007).
180. Farmer, H. et al., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (7035), 917 (2005).
181. Edwards, S. L. et al., Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451 (7182), 1111 (2008).
182. Sakai, W. et al., Secondary mutations as a mechanism of cisplatin resistance in BRCA2- mutated cancers. Nature 451 (7182), 1116 (2008).
183. Swisher, E. M. et al., Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 68 (8), 2581 (2008).