Association of BRCA1 with the inactive X chromosome and XIST RNA.
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.
Ganesan
Shridar
S
The Dana-Farber Cancer Institute and Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Silver
Daniel P
DP
Drapkin
Ronny
R
Greenberg
Roger
R
Feunteun
Jean
J
Livingston
David M
DM
D002843:Chromatin / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008957:Models, Genetic; D011233:Precipitin Tests; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D008164:Luminescent Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA; D049452:Green Fluorescent Proteins