BRCA1 localization to the telomere and its loss upon DNA damage
Thesis (Ph.D.)--Georgetown University, 2010.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. BRCA1, a tumor suppressor, participates in DNA damage signaling and repair. Previously, we showed that BRCA1 over-expression caused inhibition of telomerase activity and telomere shortening in breast and prostate cancer cells. We now report that BRCA1 knockdown causes increased telomerase reverse transcriptase (TERT) expression, telomerase activity, and telomere length. Studies utilizing a combination of BRCA1 and TERT siRNAs suggest that BRCA1 also regulates telomere length independently of telomerase. Using telomeric ChIP assays, we detected BRCA1 at the telomere and demonstrated time-dependent loss of BRCA1 from the telomere following DNA damage. Further studies suggest that BRCA1 interacts with TRF1 and TRF2 in a DNA-dependent manner and that some of the nuclear BRCA1 colocalizes with TRF1/2. Our findings further suggest that Rad50 is required to localize BRCA1 at the telomere and that the association of BRCA1 with Rad50 does not require DNA. Finally, we found that BRCA1 regulates the length of the 3' G-rich overhang in a manner that is dependent upon Rad50. Our findings suggest that BRCA1 is recruited to the telomere in a Rad-50-dependent manner and that BRCA1 may regulate telomere length and stability through its presence at the telomere.
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