BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage
BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage
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DOI：
10.1074/jbc.m109.025825
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Rosen, Eliot M.
中科院分区：
文献类型：
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作者：
Ballal, Rahul D.;Saha, Tapas;Rosen, Eliot M.
BRCA 1是一种肿瘤抑制因子，参与DNA损伤信号传导和修复。以前，我们发现BRCA 1过表达导致乳腺癌和前列腺癌细胞端粒酶活性抑制和端粒缩短。我们现在报告说，BRCA 1敲低导致端粒酶逆转录酶表达，端粒酶活性和端粒长度增加，但研究利用BRCA 1和端粒酶逆转录酶小干扰RNA的组合表明，BRCA 1也调节端粒长度独立于端粒酶。使用端粒染色质免疫沉淀法，我们检测到BRCA 1在端粒和证明BRCA 1从端粒DNA损伤后的时间依赖性损失。进一步的研究表明，BRCA 1与TRF 1和TRF 2以DNA依赖的方式相互作用，并且一些核BRCA 1与TRF 1/2共定位。我们的研究结果进一步表明，Rad 50是需要本地化BRCA 1在端粒和协会的BRCA 1与Rad 50不需要DNA。最后，我们发现BRCA 1以依赖于Rad 50的方式调节富含3'G的突出端的长度。我们的研究结果表明，BRCA 1被招募到端粒中的Rad 50依赖的方式，BRCA 1可以调节端粒的长度和稳定性，部分通过其存在于端粒。
BRCA1, a tumor suppressor, participates in DNA damage signaling and repair. Previously, we showed that BRCA1 overexpression 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 expression, telomerase activity, and telomere length; but studies utilizing a combination of BRCA1 and telomerase reverse transcriptase small interfering RNAs suggest that BRCA1 also regulates telomere length independently of telomerase. Using telomeric chromatin immunoprecipitation 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 Rad50-dependent manner and that BRCA1 may regulate telomere length and stability, in part through its presence at the telomere.