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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Feb 29;355(1394):191–198. doi: 10.1098/rstb.2000.0558

The breast cancer susceptibility gene, BRCA2: at the crossroads between DNA replication and recombination?

A R Venkitaraman 1
PMCID: PMC1692733  PMID: 10724455

Abstract

The identification and cloning of the familial breast cancer susceptibility gene, BRCA2, has excited much interest in its biological functions. Here, evidence is reviewed that the protein encoded by BRCA2 has an essential role in DNA repair through its association with mRad51, a mammalian homologue of bacterial and yeast proteins involved in homologous recombination. A model is proposed that the critical requirement for BRCA2 in cell division and the maintenance of chromosome stability stems from its participation in recombinational processes essential for DNA replication.

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Selected References

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  1. Albala J. S., Thelen M. P., Prange C., Fan W., Christensen M., Thompson L. H., Lennon G. G. Identification of a novel human RAD51 homolog, RAD51B. Genomics. 1997 Dec 15;46(3):476–479. doi: 10.1006/geno.1997.5062. [DOI] [PubMed] [Google Scholar]
  2. Baumann P., Benson F. E., West S. C. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell. 1996 Nov 15;87(4):757–766. doi: 10.1016/s0092-8674(00)81394-x. [DOI] [PubMed] [Google Scholar]
  3. Benson F. E., Baumann P., West S. C. Synergistic actions of Rad51 and Rad52 in recombination and DNA repair. Nature. 1998 Jan 22;391(6665):401–404. doi: 10.1038/34937. [DOI] [PubMed] [Google Scholar]
  4. Bertwistle D., Swift S., Marston N. J., Jackson L. E., Crossland S., Crompton M. R., Marshall C. J., Ashworth A. Nuclear location and cell cycle regulation of the BRCA2 protein. Cancer Res. 1997 Dec 15;57(24):5485–5488. [PubMed] [Google Scholar]
  5. Bezzubova O., Silbergleit A., Yamaguchi-Iwai Y., Takeda S., Buerstedde J. M. Reduced X-ray resistance and homologous recombination frequencies in a RAD54-/- mutant of the chicken DT40 cell line. Cell. 1997 Apr 18;89(2):185–193. doi: 10.1016/s0092-8674(00)80198-1. [DOI] [PubMed] [Google Scholar]
  6. Bignell G., Micklem G., Stratton M. R., Ashworth A., Wooster R. The BRC repeats are conserved in mammalian BRCA2 proteins. Hum Mol Genet. 1997 Jan;6(1):53–58. doi: 10.1093/hmg/6.1.53. [DOI] [PubMed] [Google Scholar]
  7. Bishop D. K., Park D., Xu L., Kleckner N. DMC1: a meiosis-specific yeast homolog of E. coli recA required for recombination, synaptonemal complex formation, and cell cycle progression. Cell. 1992 May 1;69(3):439–456. doi: 10.1016/0092-8674(92)90446-j. [DOI] [PubMed] [Google Scholar]
  8. Bork P., Blomberg N., Nilges M. Internal repeats in the BRCA2 protein sequence. Nat Genet. 1996 May;13(1):22–23. doi: 10.1038/ng0596-22. [DOI] [PubMed] [Google Scholar]
  9. Cartwright R., Tambini C. E., Simpson P. J., Thacker J. The XRCC2 DNA repair gene from human and mouse encodes a novel member of the recA/RAD51 family. Nucleic Acids Res. 1998 Jul 1;26(13):3084–3089. doi: 10.1093/nar/26.13.3084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chapman M. S., Verma I. M. Transcriptional activation by BRCA1. Nature. 1996 Aug 22;382(6593):678–679. doi: 10.1038/382678a0. [DOI] [PubMed] [Google Scholar]
  11. Chen C., Umezu K., Kolodner R. D. Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol Cell. 1998 Jul;2(1):9–22. doi: 10.1016/s1097-2765(00)80109-4. [DOI] [PubMed] [Google Scholar]
  12. Chen P. L., Chen C. F., Chen Y., Xiao J., Sharp Z. D., Lee W. H. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5287–5292. doi: 10.1073/pnas.95.9.5287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cheong N., Wang X., Wang Y., Iliakis G. Loss of S-phase-dependent radioresistance in irs-1 cells exposed to X-rays. Mutat Res. 1994 Jan;314(1):77–85. doi: 10.1016/0921-8777(94)90063-9. [DOI] [PubMed] [Google Scholar]
  14. Collins N., McManus R., Wooster R., Mangion J., Seal S., Lakhani S. R., Ormiston W., Daly P. A., Ford D., Easton D. F. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene. 1995 Apr 20;10(8):1673–1675. [PubMed] [Google Scholar]
  15. Connor F., Bertwistle D., Mee P. J., Ross G. M., Swift S., Grigorieva E., Tybulewicz V. L., Ashworth A. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet. 1997 Dec;17(4):423–430. doi: 10.1038/ng1297-423. [DOI] [PubMed] [Google Scholar]
  16. Courcelle J., Carswell-Crumpton C., Hanawalt P. C. recF and recR are required for the resumption of replication at DNA replication forks in Escherichia coli. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3714–3719. doi: 10.1073/pnas.94.8.3714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cox M. M. Recombinational crossroads: eukaryotic enzymes and the limits of bacterial precedents. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):11764–11766. doi: 10.1073/pnas.94.22.11764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dosanjh M. K., Collins D. W., Fan W., Lennon G. G., Albala J. S., Shen Z., Schild D. Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes. Nucleic Acids Res. 1998 Mar 1;26(5):1179–1184. doi: 10.1093/nar/26.5.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Essers J., Hendriks R. W., Swagemakers S. M., Troelstra C., de Wit J., Bootsma D., Hoeijmakers J. H., Kanaar R. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell. 1997 Apr 18;89(2):195–204. doi: 10.1016/s0092-8674(00)80199-3. [DOI] [PubMed] [Google Scholar]
  20. Friedman L. S., Thistlethwaite F. C., Patel K. J., Yu V. P., Lee H., Venkitaraman A. R., Abel K. J., Carlton M. B., Hunter S. M., Colledge W. H. Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res. 1998 Apr 1;58(7):1338–1343. [PubMed] [Google Scholar]
  21. Fuks F., Milner J., Kouzarides T. BRCA2 associates with acetyltransferase activity when bound to P/CAF. Oncogene. 1998 Nov 12;17(19):2531–2534. doi: 10.1038/sj.onc.1202475. [DOI] [PubMed] [Google Scholar]
  22. Gayther S. A., Mangion J., Russell P., Seal S., Barfoot R., Ponder B. A., Stratton M. R., Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103–105. doi: 10.1038/ng0197-103. [DOI] [PubMed] [Google Scholar]
  23. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore) 1993 Nov;72(6):393–406. [PubMed] [Google Scholar]
  24. Gowen L. C., Avrutskaya A. V., Latour A. M., Koller B. H., Leadon S. A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science. 1998 Aug 14;281(5379):1009–1012. doi: 10.1126/science.281.5379.1009. [DOI] [PubMed] [Google Scholar]
  25. Gowen L. C., Johnson B. L., Latour A. M., Sulik K. K., Koller B. H. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet. 1996 Feb;12(2):191–194. doi: 10.1038/ng0296-191. [DOI] [PubMed] [Google Scholar]
  26. Gudmundsson J., Johannesdottir G., Arason A., Bergthorsson J. T., Ingvarsson S., Egilsson V., Barkardottir R. B. Frequent occurrence of BRCA2 linkage in Icelandic breast cancer families and segregation of a common BRCA2 haplotype. Am J Hum Genet. 1996 Apr;58(4):749–756. [PMC free article] [PubMed] [Google Scholar]
  27. Gudmundsson J., Johannesdottir G., Bergthorsson J. T., Arason A., Ingvarsson S., Egilsson V., Barkardottir R. B. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13. Cancer Res. 1995 Nov 1;55(21):4830–4832. [PubMed] [Google Scholar]
  28. Gupta R. C., Bazemore L. R., Golub E. I., Radding C. M. Activities of human recombination protein Rad51. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):463–468. doi: 10.1073/pnas.94.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Haber J. E. A super new twist on the initiation of meiotic recombination. Cell. 1997 Apr 18;89(2):163–166. doi: 10.1016/s0092-8674(00)80194-4. [DOI] [PubMed] [Google Scholar]
  30. Hakem R., de la Pompa J. L., Sirard C., Mo R., Woo M., Hakem A., Wakeham A., Potter J., Reitmair A., Billia F. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996 Jun 28;85(7):1009–1023. doi: 10.1016/s0092-8674(00)81302-1. [DOI] [PubMed] [Google Scholar]
  31. Jackson S. P., Jeggo P. A. DNA double-strand break repair and V(D)J recombination: involvement of DNA-PK. Trends Biochem Sci. 1995 Oct;20(10):412–415. doi: 10.1016/s0968-0004(00)89090-8. [DOI] [PubMed] [Google Scholar]
  32. Johannesdottir G., Gudmundsson J., Bergthorsson J. T., Arason A., Agnarsson B. A., Eiriksdottir G., Johannsson O. T., Borg A., Ingvarsson S., Easton D. F. High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res. 1996 Aug 15;56(16):3663–3665. [PubMed] [Google Scholar]
  33. Jones N. J., Cox R., Thacker J. Isolation and cross-sensitivity of X-ray-sensitive mutants of V79-4 hamster cells. Mutat Res. 1987 May;183(3):279–286. doi: 10.1016/0167-8817(87)90011-3. [DOI] [PubMed] [Google Scholar]
  34. Keeney S., Giroux C. N., Kleckner N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell. 1997 Feb 7;88(3):375–384. doi: 10.1016/s0092-8674(00)81876-0. [DOI] [PubMed] [Google Scholar]
  35. Kogoma T. Recombination by replication. Cell. 1996 May 31;85(5):625–627. doi: 10.1016/s0092-8674(00)81229-5. [DOI] [PubMed] [Google Scholar]
  36. Kogoma T. Stable DNA replication: interplay between DNA replication, homologous recombination, and transcription. Microbiol Mol Biol Rev. 1997 Jun;61(2):212–238. doi: 10.1128/mmbr.61.2.212-238.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kuzminov A. Collapse and repair of replication forks in Escherichia coli. Mol Microbiol. 1995 May;16(3):373–384. doi: 10.1111/j.1365-2958.1995.tb02403.x. [DOI] [PubMed] [Google Scholar]
  38. Lee H., Trainer A. H., Friedman L. S., Thistlethwaite F. C., Evans M. J., Ponder B. A., Venkitaraman A. R. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol Cell. 1999 Jul;4(1):1–10. doi: 10.1016/s1097-2765(00)80182-3. [DOI] [PubMed] [Google Scholar]
  39. Liang F., Han M., Romanienko P. J., Jasin M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5172–5177. doi: 10.1073/pnas.95.9.5172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lim D. S., Hasty P. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol Cell Biol. 1996 Dec;16(12):7133–7143. doi: 10.1128/mcb.16.12.7133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993 Apr 22;362(6422):709–715. doi: 10.1038/362709a0. [DOI] [PubMed] [Google Scholar]
  42. Lindahl T. The Croonian Lecture, 1996: endogenous damage to DNA. Philos Trans R Soc Lond B Biol Sci. 1996 Nov 29;351(1347):1529–1538. doi: 10.1098/rstb.1996.0139. [DOI] [PubMed] [Google Scholar]
  43. Liu C. Y., Flesken-Nikitin A., Li S., Zeng Y., Lee W. H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 1996 Jul 15;10(14):1835–1843. doi: 10.1101/gad.10.14.1835. [DOI] [PubMed] [Google Scholar]
  44. Liu J., Xu L., Sandler S. J., Marians K. J. Replication fork assembly at recombination intermediates is required for bacterial growth. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3552–3555. doi: 10.1073/pnas.96.7.3552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Liu N., Lamerdin J. E., Tebbs R. S., Schild D., Tucker J. D., Shen M. R., Brookman K. W., Siciliano M. J., Walter C. A., Fan W. XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Mol Cell. 1998 May;1(6):783–793. doi: 10.1016/s1097-2765(00)80078-7. [DOI] [PubMed] [Google Scholar]
  46. Ludwig T., Chapman D. L., Papaioannou V. E., Efstratiadis A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997 May 15;11(10):1226–1241. doi: 10.1101/gad.11.10.1226. [DOI] [PubMed] [Google Scholar]
  47. Malkova A., Ivanov E. L., Haber J. E. Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7131–7136. doi: 10.1073/pnas.93.14.7131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Meselson M. S., Radding C. M. A general model for genetic recombination. Proc Natl Acad Sci U S A. 1975 Jan;72(1):358–361. doi: 10.1073/pnas.72.1.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Michel B., Ehrlich S. D., Uzest M. DNA double-strand breaks caused by replication arrest. EMBO J. 1997 Jan 15;16(2):430–438. doi: 10.1093/emboj/16.2.430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  51. Mizuta R., LaSalle J. M., Cheng H. L., Shinohara A., Ogawa H., Copeland N., Jenkins N. A., Lalande M., Alt F. W. RAB22 and RAB163/mouse BRCA2: proteins that specifically interact with the RAD51 protein. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6927–6932. doi: 10.1073/pnas.94.13.6927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Neuhausen S., Gilewski T., Norton L., Tran T., McGuire P., Swensen J., Hampel H., Borgen P., Brown K., Skolnick M. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996 May;13(1):126–128. doi: 10.1038/ng0596-126. [DOI] [PubMed] [Google Scholar]
  53. New J. H., Sugiyama T., Zaitseva E., Kowalczykowski S. C. Rad52 protein stimulates DNA strand exchange by Rad51 and replication protein A. Nature. 1998 Jan 22;391(6665):407–410. doi: 10.1038/34950. [DOI] [PubMed] [Google Scholar]
  54. Ogawa T., Yu X., Shinohara A., Egelman E. H. Similarity of the yeast RAD51 filament to the bacterial RecA filament. Science. 1993 Mar 26;259(5103):1896–1899. doi: 10.1126/science.8456314. [DOI] [PubMed] [Google Scholar]
  55. Patel K. J., Yu V. P., Lee H., Corcoran A., Thistlethwaite F. C., Evans M. J., Colledge W. H., Friedman L. S., Ponder B. A., Venkitaraman A. R. Involvement of Brca2 in DNA repair. Mol Cell. 1998 Feb;1(3):347–357. doi: 10.1016/s1097-2765(00)80035-0. [DOI] [PubMed] [Google Scholar]
  56. Pittman D. L., Weinberg L. R., Schimenti J. C. Identification, characterization, and genetic mapping of Rad51d, a new mouse and human RAD51/RecA-related gene. Genomics. 1998 Apr 1;49(1):103–111. doi: 10.1006/geno.1998.5226. [DOI] [PubMed] [Google Scholar]
  57. Rahman N., Stratton M. R. The genetics of breast cancer susceptibility. Annu Rev Genet. 1998;32:95–121. doi: 10.1146/annurev.genet.32.1.95. [DOI] [PubMed] [Google Scholar]
  58. Roca A. I., Cox M. M. RecA protein: structure, function, and role in recombinational DNA repair. Prog Nucleic Acid Res Mol Biol. 1997;56:129–223. doi: 10.1016/s0079-6603(08)61005-3. [DOI] [PubMed] [Google Scholar]
  59. Rothstein R., Gangloff S. Hyper-recombination and Bloom's syndrome: microbes again provide clues about cancer. Genome Res. 1995 Dec;5(5):421–426. doi: 10.1101/gr.5.5.421. [DOI] [PubMed] [Google Scholar]
  60. Rouet P., Smih F., Jasin M. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol Cell Biol. 1994 Dec;14(12):8096–8106. doi: 10.1128/mcb.14.12.8096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T., Livingston D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997 Jan 24;88(2):265–275. doi: 10.1016/s0092-8674(00)81847-4. [DOI] [PubMed] [Google Scholar]
  62. Seigneur M., Bidnenko V., Ehrlich S. D., Michel B. RuvAB acts at arrested replication forks. Cell. 1998 Oct 30;95(3):419–430. doi: 10.1016/s0092-8674(00)81772-9. [DOI] [PubMed] [Google Scholar]
  63. Sharan S. K., Bradley A. Murine Brca2: sequence, map position, and expression pattern. Genomics. 1997 Mar 1;40(2):234–241. doi: 10.1006/geno.1996.4573. [DOI] [PubMed] [Google Scholar]
  64. Sharan S. K., Morimatsu M., Albrecht U., Lim D. S., Regel E., Dinh C., Sands A., Eichele G., Hasty P., Bradley A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997 Apr 24;386(6627):804–810. doi: 10.1038/386804a0. [DOI] [PubMed] [Google Scholar]
  65. Shinohara A., Ogawa H., Ogawa T. Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein. Cell. 1992 May 1;69(3):457–470. doi: 10.1016/0092-8674(92)90447-k. [DOI] [PubMed] [Google Scholar]
  66. Shinohara A., Shinohara M., Ohta T., Matsuda S., Ogawa T. Rad52 forms ring structures and co-operates with RPA in single-strand DNA annealing. Genes Cells. 1998 Mar;3(3):145–156. doi: 10.1046/j.1365-2443.1998.00176.x. [DOI] [PubMed] [Google Scholar]
  67. Sonoda E., Sasaki M. S., Buerstedde J. M., Bezzubova O., Shinohara A., Ogawa H., Takata M., Yamaguchi-Iwai Y., Takeda S. Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J. 1998 Jan 15;17(2):598–608. doi: 10.1093/emboj/17.2.598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Stamato T. D., Dipatri A., Giaccia A. Cell-cycle-dependent repair of potentially lethal damage in the XR-1 gamma-ray-sensitive Chinese hamster ovary cell. Radiat Res. 1988 Aug;115(2):325–333. [PubMed] [Google Scholar]
  69. Stürzbecher H. W., Donzelmann B., Henning W., Knippschild U., Buchhop S. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J. 1996 Apr 15;15(8):1992–2002. [PMC free article] [PubMed] [Google Scholar]
  70. Sung P. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein. Science. 1994 Aug 26;265(5176):1241–1243. doi: 10.1126/science.8066464. [DOI] [PubMed] [Google Scholar]
  71. Sung P. Function of yeast Rad52 protein as a mediator between replication protein A and the Rad51 recombinase. J Biol Chem. 1997 Nov 7;272(45):28194–28197. doi: 10.1074/jbc.272.45.28194. [DOI] [PubMed] [Google Scholar]
  72. Sung P., Robberson D. L. DNA strand exchange mediated by a RAD51-ssDNA nucleoprotein filament with polarity opposite to that of RecA. Cell. 1995 Aug 11;82(3):453–461. doi: 10.1016/0092-8674(95)90434-4. [DOI] [PubMed] [Google Scholar]
  73. Sung P., Stratton S. A. Yeast Rad51 recombinase mediates polar DNA strand exchange in the absence of ATP hydrolysis. J Biol Chem. 1996 Nov 8;271(45):27983–27986. doi: 10.1074/jbc.271.45.27983. [DOI] [PubMed] [Google Scholar]
  74. Suzuki A., de la Pompa J. L., Hakem R., Elia A., Yoshida R., Mo R., Nishina H., Chuang T., Wakeham A., Itie A. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997 May 15;11(10):1242–1252. doi: 10.1101/gad.11.10.1242. [DOI] [PubMed] [Google Scholar]
  75. Szostak J. W., Orr-Weaver T. L., Rothstein R. J., Stahl F. W. The double-strand-break repair model for recombination. Cell. 1983 May;33(1):25–35. doi: 10.1016/0092-8674(83)90331-8. [DOI] [PubMed] [Google Scholar]
  76. Takata M., Sasaki M. S., Sonoda E., Morrison C., Hashimoto M., Utsumi H., Yamaguchi-Iwai Y., Shinohara A., Takeda S. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998 Sep 15;17(18):5497–5508. doi: 10.1093/emboj/17.18.5497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Tavtigian S. V., Simard J., Rommens J., Couch F., Shattuck-Eidens D., Neuhausen S., Merajver S., Thorlacius S., Offit K., Stoppa-Lyonnet D. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333–337. doi: 10.1038/ng0396-333. [DOI] [PubMed] [Google Scholar]
  78. Thorlacius S., Olafsdottir G., Tryggvadottir L., Neuhausen S., Jonasson J. G., Tavtigian S. V., Tulinius H., Ogmundsdottir H. M., Eyfjörd J. E. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996 May;13(1):117–119. doi: 10.1038/ng0596-117. [DOI] [PubMed] [Google Scholar]
  79. Tsuzuki T., Fujii Y., Sakumi K., Tominaga Y., Nakao K., Sekiguchi M., Matsushiro A., Yoshimura Y., MoritaT Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6236–6240. doi: 10.1073/pnas.93.13.6236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. West S. C., Cassuto E., Howard-Flanders P. Mechanism of E. coli RecA protein directed strand exchanges in post-replication repair of DNA. Nature. 1981 Dec 17;294(5842):659–662. doi: 10.1038/294659a0. [DOI] [PubMed] [Google Scholar]
  81. Whitmore G. F., Varghese A. J., Gulyas S. Cell cycle responses of two X-ray sensitive mutants defective in DNA repair. Int J Radiat Biol. 1989 Nov;56(5):657–665. doi: 10.1080/09553008914551881. [DOI] [PubMed] [Google Scholar]
  82. Wong A. K., Pero R., Ormonde P. A., Tavtigian S. V., Bartel P. L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem. 1997 Dec 19;272(51):31941–31944. doi: 10.1074/jbc.272.51.31941. [DOI] [PubMed] [Google Scholar]
  83. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]
  84. Wooster R., Neuhausen S. L., Mangion J., Quirk Y., Ford D., Collins N., Nguyen K., Seal S., Tran T., Averill D. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994 Sep 30;265(5181):2088–2090. doi: 10.1126/science.8091231. [DOI] [PubMed] [Google Scholar]
  85. Xu X., Weaver Z., Linke S. P., Li C., Gotay J., Wang X. W., Harris C. C., Ried T., Deng C. X. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999 Mar;3(3):389–395. doi: 10.1016/s1097-2765(00)80466-9. [DOI] [PubMed] [Google Scholar]
  86. Zou H., Rothstein R. Holliday junctions accumulate in replication mutants via a RecA homolog-independent mechanism. Cell. 1997 Jul 11;90(1):87–96. doi: 10.1016/s0092-8674(00)80316-5. [DOI] [PubMed] [Google Scholar]

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