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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 Jan 29;359(1441):123–128. doi: 10.1098/rstb.2003.1371

Association of BRCA1 with the inactive X chromosome and XIST RNA.

Shridar Ganesan 1, Daniel P Silver 1, Ronny Drapkin 1, Roger Greenberg 1, Jean Feunteun 1, David M Livingston 1
PMCID: PMC1693294  PMID: 15065664

Abstract

Breast cancer, early onset 1 (BRCA1) encodes a nuclear protein that participates in breast and ovarian cancer suppression. The molecular basis for the gender and tissue specificity of the BRCA1 cancer syndrome is unknown. Recently, we observed that a fraction of BRCA1 in female cells is localized on the inactive X chromosome (Xi). Chromatin immunoprecipitation (ChIP) experiments have demonstrated that BRCA1 physically associates with Xi-specific transcript (XIST) RNA, a non-coding RNA known to coat Xi and to participate in the initiation of its inactivation during early embryogenesis. Cells lacking wild-type BRCA1 show abnormalities in Xi, including lack of proper XIST RNA localization. Reintroduction of wild-type, but not mutant, BRCA1 can correct this defect in XIST localization in these cells. Depletion of BRCA1 in female diploid cells led to a defect in proper XIST localization on Xi and in the development of normal Xi heterchromatic superstructure. Moreover, depletion of BRCA1 led to an increased likelihood of re-expression of a green fluorescent protein (GFP) reporter gene embedded on Xi. Taken together, these findings are consistent with a model in which BRCA1 function contributes to the maintenance of proper Xi heterochromatin superstructure. Although the data imply a novel gender-specific consequence of BRCA1 loss, the relevance of the BRCA1/Xi function to the tumour suppressor activity of BRCA1 remains unclear and needs to be tested.

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Selected References

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  1. Avner P., Heard E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet. 2001 Jan;2(1):59–67. doi: 10.1038/35047580. [DOI] [PubMed] [Google Scholar]
  2. Ayoub N., Richler C., Wahrman J. Xist RNA is associated with the transcriptionally inactive XY body in mammalian male meiosis. Chromosoma. 1997 Jun;106(1):1–10. doi: 10.1007/s004120050218. [DOI] [PubMed] [Google Scholar]
  3. Bochar D. A., Wang L., Beniya H., Kinev A., Xue Y., Lane W. S., Wang W., Kashanchi F., Shiekhattar R. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell. 2000 Jul 21;102(2):257–265. doi: 10.1016/s0092-8674(00)00030-1. [DOI] [PubMed] [Google Scholar]
  4. Clemson C. M., McNeil J. A., Willard H. F., Lawrence J. B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol. 1996 Feb;132(3):259–275. doi: 10.1083/jcb.132.3.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Costanzi C., Pehrson J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature. 1998 Jun 11;393(6685):599–601. doi: 10.1038/31275. [DOI] [PubMed] [Google Scholar]
  6. Csankovszki G., Nagy A., Jaenisch R. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 2001 May 14;153(4):773–784. doi: 10.1083/jcb.153.4.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Deng C. X., Brodie S. G. Roles of BRCA1 and its interacting proteins. Bioessays. 2000 Aug;22(8):728–737. doi: 10.1002/1521-1878(200008)22:8<728::AID-BIES6>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  8. Fan S., Ma Y. X., Wang C., Yuan R. Q., Meng Q., Wang J. A., Erdos M., Goldberg I. D., Webb P., Kushner P. J. Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene. 2001 Jan 4;20(1):77–87. doi: 10.1038/sj.onc.1204073. [DOI] [PubMed] [Google Scholar]
  9. Ganesan Shridar, Silver Daniel P., Greenberg Roger A., Avni Dror, Drapkin Ronny, Miron Alexander, Mok Samuel C., Randrianarison Voahangy, Brodie Steven, Salstrom Jennifer. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002 Nov 1;111(3):393–405. doi: 10.1016/s0092-8674(02)01052-8. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Handel M. A., Hunt P. A. Sex-chromosome pairing and activity during mammalian meiosis. Bioessays. 1992 Dec;14(12):817–822. doi: 10.1002/bies.950141205. [DOI] [PubMed] [Google Scholar]
  12. Harkin D. P., Bean J. M., Miklos D., Song Y. H., Truong V. B., Englert C., Christians F. C., Ellisen L. W., Maheswaran S., Oliner J. D. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell. 1999 May 28;97(5):575–586. doi: 10.1016/s0092-8674(00)80769-2. [DOI] [PubMed] [Google Scholar]
  13. Huynh K. D., Lee J. T. Imprinted X inactivation in eutherians: a model of gametic execution and zygotic relaxation. Curr Opin Cell Biol. 2001 Dec;13(6):690–697. doi: 10.1016/s0955-0674(00)00272-6. [DOI] [PubMed] [Google Scholar]
  14. Jaenisch R., Beard C., Lee J., Marahrens Y., Panning B. Mammalian X chromosome inactivation. Novartis Found Symp. 1998;214:200-9; discussion 209-13, 228-32. doi: 10.1002/9780470515501.ch12. [DOI] [PubMed] [Google Scholar]
  15. Jazaeri Amir A., Yee Cindy J., Sotiriou Christos, Brantley Kelly R., Boyd Jeff, Liu Edison T. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst. 2002 Jul 3;94(13):990–1000. doi: 10.1093/jnci/94.13.990. [DOI] [PubMed] [Google Scholar]
  16. Kelley R. L., Kuroda M. I. Noncoding RNA genes in dosage compensation and imprinting. Cell. 2000 Sep 29;103(1):9–12. doi: 10.1016/s0092-8674(00)00099-4. [DOI] [PubMed] [Google Scholar]
  17. MOORE K. L., BARR M. L. The sex chromatin in human malignant tissues. Br J Cancer. 1957 Sep;11(3):384–390. doi: 10.1038/bjc.1957.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maison Christèle, Bailly Delphine, Peters Antoine H. F. M., Quivy Jean-Pierre, Roche Danièle, Taddei Angela, Lachner Monika, Jenuwein Thomas, Almouzni Geneviève. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nat Genet. 2002 Feb 19;30(3):329–334. doi: 10.1038/ng843. [DOI] [PubMed] [Google Scholar]
  19. Moynahan M. E., Chiu J. W., Koller B. H., Jasin M. Brca1 controls homology-directed DNA repair. Mol Cell. 1999 Oct;4(4):511–518. doi: 10.1016/s1097-2765(00)80202-6. [DOI] [PubMed] [Google Scholar]
  20. Perry M. Evaluation of breast tumour sex chromatin (Barr body) as an index of survival and response to pituitary ablation. Br J Surg. 1972 Sep;59(9):731–734. doi: 10.1002/bjs.1800590912. [DOI] [PubMed] [Google Scholar]
  21. Richler C., Dhara S. K., Wahrman J. Histone macroH2A1.2 is concentrated in the XY compartment of mammalian male meiotic nuclei. Cytogenet Cell Genet. 2000;89(1-2):118–120. doi: 10.1159/000015589. [DOI] [PubMed] [Google Scholar]
  22. Richler C., Soreq H., Wahrman J. X inactivation in mammalian testis is correlated with inactive X-specific transcription. Nat Genet. 1992 Nov;2(3):192–195. doi: 10.1038/ng1192-192. [DOI] [PubMed] [Google Scholar]
  23. Rosen P. P., Savino A., Menendez-Botet C., Urban J. A., Mike V., Schwartz M. K., Melamed M. R. Barr body distribution and estrogen receptor protein in mammary carcinoma. Ann Clin Lab Sci. 1977 Nov-Dec;7(6):491–499. [PubMed] [Google Scholar]
  24. Rudas M., Schmidinger M., Wenzel C., Okamoto I., Budinsky A., Fazeny B., Marosi C. Karyotypic findings in two cases of male breast cancer. Cancer Genet Cytogenet. 2000 Sep;121(2):190–193. doi: 10.1016/s0165-4608(00)00254-5. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Scully R., Ganesan S., Brown M., De Caprio J. A., Cannistra S. A., Feunteun J., Schnitt S., Livingston D. M. Location of BRCA1 in human breast and ovarian cancer cells. Science. 1996 Apr 5;272(5258):123–126. doi: 10.1126/science.272.5258.123. [DOI] [PubMed] [Google Scholar]
  27. Scully R., Ganesan S., Vlasakova K., Chen J., Socolovsky M., Livingston D. M. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell. 1999 Dec;4(6):1093–1099. doi: 10.1016/s1097-2765(00)80238-5. [DOI] [PubMed] [Google Scholar]
  28. Scully R., Livingston D. M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 2000 Nov 23;408(6811):429–432. doi: 10.1038/35044000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Swerdlow A. J., Hermon C., Jacobs P. A., Alberman E., Beral V., Daker M., Fordyce A., Youings S. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet. 2001 Mar;65(Pt 2):177–188. doi: 10.1017/S0003480001008569. [DOI] [PubMed] [Google Scholar]
  30. Teixeira M. R., Pandis N., Dietrich C. U., Reed W., Andersen J., Qvist H., Heim S. Chromosome banding analysis of gynecomastias and breast carcinomas in men. Genes Chromosomes Cancer. 1998 Sep;23(1):16–20. doi: 10.1002/(sici)1098-2264(199809)23:1<16::aid-gcc3>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  31. Thompson Deborah, Easton Douglas F., Breast Cancer Linkage Consortium Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002 Sep 18;94(18):1358–1365. doi: 10.1093/jnci/94.18.1358. [DOI] [PubMed] [Google Scholar]
  32. Venkitaraman Ashok R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171–182. doi: 10.1016/s0092-8674(02)00615-3. [DOI] [PubMed] [Google Scholar]
  33. Ye Q., Hu Y. F., Zhong H., Nye A. C., Belmont A. S., Li R. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 2001 Dec 10;155(6):911–921. doi: 10.1083/jcb.200108049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zheng L., Pan H., Li S., Flesken-Nikitin A., Chen P. L., Boyer T. G., Lee W. H. Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell. 2000 Oct;6(4):757–768. doi: 10.1016/s1097-2765(00)00075-7. [DOI] [PubMed] [Google Scholar]

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