Journal of Molecular Medicine

, Volume 81, Issue 11, pp 700–707

BRCA1 and p53: compensatory roles in DNA repair

Invited Review

Abstract

The BRCA1 breast cancer susceptibility gene has been implicated in many cellular processes, yet its specific mechanism of tumor suppression remains unclear. BRCA1 plays a role in several DNA repair pathways including nucleotide excision repair (NER). Loss of the p53 tumor suppressor gene, a key regulator of NER, is an important and necessary event in the pathogenesis of BRCA1-mutated tumors. Here we discuss the role of BRCA1 and NER in breast cancer and the interactions of BRCA1 with p53 in breast tumorigenesis and suggest approaches for risk assessment and chemotherapeutic management of BRCA1-related breast cancer.

Keywords

BRCA1 p53 Nucleotide excision repair Breast cancer 

Abbreviations

BPDE

Benzo[a]pyrene-7,8-diol-9,10-epoxide

ER

Estrogen receptor

FA

Fanconi anemia

GGR

Global genomic repair

IR

Ionizing radiation

NER

Nucleotide excision repair

TCR

Transcription-coupled repair

UV

Ultraviolet

XP

Xeroderma pigmentosum

References

  1. 1.
    Ford D, et al (1994) Risks of cancer in BRCA1 mutation carriers. Lancet 343:692–695PubMedGoogle Scholar
  2. 2.
    Easton DF, Ford D, Bishop DT (1995) Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet 56:65–71Google Scholar
  3. 3.
    Chappuis PO, et al (2000) Germline BRCA1/2 mutations and p27 (Kip1) protein levels independently predict outcome after breast cancer. J Clin Oncol 18:4045–4052Google Scholar
  4. 4.
    Stoppa-Lyonnet D, et al (2000) Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18:4053–4059Google Scholar
  5. 5.
    Hedenfalk I, et al (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344:539–548PubMedGoogle Scholar
  6. 6.
    Lakhani SR, et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310–2318Google Scholar
  7. 7.
    Miyamoto K, et al (2002) Promoter hypermethylation and post-transcriptional mechanisms for reduced BRCA1 immunoreactivity in sporadic human breast cancers. Jpn J Clin Oncol 32:79–84CrossRefPubMedGoogle Scholar
  8. 8.
    Esteller M, et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–584PubMedGoogle Scholar
  9. 9.
    Bianco T, et al (2000) Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis 21:147–184Google Scholar
  10. 10.
    Rice JC, et al (2000) Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 21:1761–1784Google Scholar
  11. 11.
    Schuyer M, Berns EM (1999) Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Mol Cell Endocrinol 155:143–152Google Scholar
  12. 12.
    Crook T, et al (1998) p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene 17:1681–1689Google Scholar
  13. 13.
    Hakem R, et al (1997) Partial rescue of Brca1 (5–6) early embryonic lethality by p53 or p21 null mutation. Nat Genet 16:298–302Google Scholar
  14. 14.
    Hakem R, et al (1996) The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85:1009–1023PubMedGoogle Scholar
  15. 15.
    MacLachlan TK, et al (2000) BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. J Biol Chem 275:2777–2785PubMedGoogle Scholar
  16. 16.
    Arizti P, et al (2000) Tumor suppressor p53 is required to modulate BRCA1 expression. Mol Cell Biol 20:7450–7459Google Scholar
  17. 17.
    Brodie S, et al (2001) Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene 20:7514–7523Google Scholar
  18. 18.
    Deng C, Brodie S (2001) Knockout mouse models and mammary tumorigenesis. Semin Cancer Biol 11:387–394Google Scholar
  19. 19.
    Ford JM, Hanawalt PC (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci U S A 92:8876–8880Google Scholar
  20. 20.
    Ford JM, Hanawalt PC (1997) Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J Biol Chem 272:28073–28080Google Scholar
  21. 21.
    Lloyd DR, Hanawalt PC (2000) p53-dependent global genomic repair of benzo[a]pyrene-7:8-diol-9:10-epoxide adducts in human cells. Cancer Res 60:517–521Google Scholar
  22. 22.
    Ford J, Hanawalt P (1997) Role of DNA excision repair gene defects in the etiology of cancer. Curr Top Microbiol Immunol 221:47–70Google Scholar
  23. 23.
    Wood RD (1997) Nucleotide excision repair in mammalian cells. J Biol Chem 272:23465–23468CrossRefPubMedGoogle Scholar
  24. 24.
    Wood RD (1999) DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie 81:39–44Google Scholar
  25. 25.
    Greenblatt MS, et al (2001) TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res 61:4092–4097Google Scholar
  26. 26.
    Motykiewicz G, et al (2001) Immunoperoxidase detection of polycyclic aromatic hydrocarbon-DNA adducts in breast tissue sections. Cancer Detect Prev 25:328–335Google Scholar
  27. 27.
    Xiong P, et al (2001) Sensitivity to benzo(a)pyrene diol-epoxide associated with risk of breast cancer in young women and modulation by glutathione S-transferase polymorphisms: a case-control study. Cancer Res 61:8465–8469Google Scholar
  28. 28.
    Kumar R, et al (2003) Single nucleotide polymorphisms in the XPG gene: determination of role in DNA repair and breast cancer risk. Int J Cancer 103:671–675Google Scholar
  29. 29.
    Tang D, et al (2002) Polymorphisms in the DNA repair enzyme XPD are associated with increased levels of PAH-DNA adducts in a case-control study of breast cancer. Breast Cancer Res Treat 75:159–166Google Scholar
  30. 30.
    Takebayashi Y, et al (2001) Loss of heterozygosity of nucleotide excision repair factors in sporadic ovarian, colon and lung carcinomas: implication for their roles of carcinogenesis in human solid tumors. Cancer Lett 174:115–125Google Scholar
  31. 31.
    Miyashita H, et al (2001) Loss of heterozygosity of nucleotide excision repair factors in sporadic oral squamous cell carcinoma using microdissected tissue. Oncol Rep 8:1133–1138Google Scholar
  32. 32.
    Adimoolam S, Ford JM (2003) p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (in press)Google Scholar
  33. 33.
    Kastan M, et al (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311PubMedGoogle Scholar
  34. 34.
    Ford JM, Baron EL, Hanawalt PC (1998) Human fibroblasts expressing the human papillomavirus E6 gene are deficient in global genomic nucleotide excision repair and sensitive to ultraviolet irradiation. Cancer Res 58:599–603Google Scholar
  35. 35.
    Hwang BJ, et al (1999) Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci U S A 96:424–428Google Scholar
  36. 36.
    Smith ML, et al (2000) p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol 20:3705–3714Google Scholar
  37. 37.
    Adimoolam S, Lin CX, Ford JM (2001) The p53-regulated cyclin-dependent kinase inhibitor, p21 (cip1, waf1, sdi1) is not required for global genomic and transcription-coupled nucleotide excision repair of UV-induced DNA photoproducts. J Biol Chem 276:25813–25822Google Scholar
  38. 38.
    Fitch ME, Cross IV, Ford JM (2003) p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation induced DNA damage, in vivo. Carcinogenesis 24:843–850Google Scholar
  39. 39.
    Adimoolam S, Ford JM (2002) p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci USA 99:12985–12990Google Scholar
  40. 40.
    Wang X, et al (1995) p53 modulation of TFIIH-associated nucleotide excision repair activity. Nat Genet 10:188–195Google Scholar
  41. 41.
    Wang X, et al (1996) The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Genes Dev 10:1219–1232Google Scholar
  42. 42.
    Hartman A, Ford J (2002) BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet 32:180–184Google Scholar
  43. 43.
    Harkin D, et al (1999) Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97:575–586PubMedGoogle Scholar
  44. 44.
    Zheng L, et al (2000) Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell 6:757–768Google Scholar
  45. 45.
    Li S, et al (2000) Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406:210–215Google Scholar
  46. 46.
    Jin S, et al (2000) BRCA1 activation of the GADD45 promoter. Oncogene 19:4050–4057Google Scholar
  47. 47.
    Takimoto R, et al (2002) BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation. Cancer Biol Ther 1:177–186Google Scholar
  48. 48.
    Abbott DW, et al (1999) BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem 274:18808–18812PubMedGoogle Scholar
  49. 49.
    Pierce LJ, et al (2000) Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18:3360–3369Google Scholar
  50. 50.
    Gowen LC, et al (1998) BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281:1009–1012Google Scholar
  51. 51.
    Gowen LC, et al (2003) Retraction. Science 300:1657Google Scholar
  52. 52.
    Le Page F, et al (2000) BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res 60:5548–5552PubMedGoogle Scholar
  53. 53.
    Harkin DP, et al (1999) Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97:575–586PubMedGoogle Scholar
  54. 54.
    Hashizume R, et al (2001) The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276:14537–14540Google Scholar
  55. 55.
    Xu B, Kim S, Kastan MB (2001) Involvement of Brca1 in S-phase and G (2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 21:3445–3450Google Scholar
  56. 56.
    Ruffner H, et al (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci U S A 98:5134–5139Google Scholar
  57. 57.
    Cortez D, et al (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286:1162–1166Google Scholar
  58. 58.
    Wang Y, et al (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14:927–939Google Scholar
  59. 59.
    Bhattacharyya A, et al (2000) 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 275:23899–23903Google Scholar
  60. 60.
    Lee J, et al (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404:201–204Google Scholar
  61. 61.
    Zhong Q, et al (1999) Association of BRCA1 with the hRad50-hMre11–p95 complex and the DNA damage response. Science 285:747–750Google Scholar
  62. 62.
    Grompe M, D'Andrea A (2001) Fanconi anemia and DNA repair. Hum Mol Genet 10:2253–2259CrossRefPubMedGoogle Scholar
  63. 63.
    Garcia-Higuera I, et al (2001) Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7:249–262PubMedGoogle Scholar
  64. 64.
    Zhen W, et al (1993) Deficient gene specific repair of cisplatin-induced lesions in xeroderma pigmentosum and Fanconi's anemia cell lines. Carcinogenesis 14:919–924Google Scholar
  65. 65.
    Moynahan M, et al (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4:511–518PubMedGoogle Scholar
  66. 66.
    Moynahan ME, Cui TY, Jasin M (2001) Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–4850Google Scholar
  67. 67.
    Scully R, et al (1999) Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell 4:1093–1099Google Scholar
  68. 68.
    Cantor S, et al (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105:149–160Google Scholar
  69. 69.
    Wang H, et al (2001) Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2. Cancer Res 61:270–277Google Scholar
  70. 70.
    Zhong Q, et al (2002) Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer Res 62:3966–3970Google Scholar
  71. 71.
    Wang H, et al (2001) Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2. Cancer Res 61:270–277Google Scholar
  72. 72.
    Merel P, et al (2002) Absence of major defects in non-homologous DNA end joining in human breast cancer cell lines. Oncogene 21:5654–5659Google Scholar
  73. 73.
    Snouwaert J, et al (1999) 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 18:7900–7907Google Scholar
  74. 74.
    Yu X, et al (1998) 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 273:25388–25392Google Scholar
  75. 75.
    Yu X, Baer R (2000) Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J Biol Chem 275:18541–18549PubMedGoogle Scholar
  76. 76.
    Li S, et al (1999) Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem 274:11334–11338Google Scholar
  77. 77.
    Zheng L, et al (2001) BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci USA 98:9587–9592Google Scholar
  78. 78.
    Ganesan S, et al (2002) BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111:393–405Google Scholar
  79. 79.
    Aunoble B, Bernard-Gallon D, Bignon YJ (2001) Regulation of BRCA1 and BRCA2 transcript in response to cisplatin, adriamycin, taxol and ionising radiation is correlated to p53 functional status in ovarian cancer cell lines. Oncol Rep 8:663–668Google Scholar
  80. 80.
    Husain A, et al (1998) BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum (II). Cancer Res 58:1120–1123Google Scholar
  81. 81.
    Moynahan ME, Cui TY, Jasin M (2001) Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–4850Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Departments of Medicine (Oncology) and Genetics, School of MedicineStanford UniversityStanfordUSA
  2. 2.Dana Farber Cancer InstituteBostonUSA

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