A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest.
A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest.
复制标题
BRCA1在两个不同的同源重组介导的修复中的双重作用，响应复制停滞。
DOI：
10.1093/nar/gkr748
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发表时间：
2012-01
影响因子：
14.9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Feng Z;Zhang J
同源重组(HR)是修复DNA复制分叉堵塞的主要机制。在这里，我们报告了由交叉相关的HR有效地产生姐妹染色单体交换(SCE)，以响应在任何可测量的DNA双链断裂(DSB)之前的复制叉停滞。有趣的是，复制检查点的中央调节因子ATR特定地抑制了DNA DSB创建后复制叉崩溃所产生的姐妹染色单体交换。BRCA1耗尽导致复制叉失速后RPA2磷酸化(RPA2-P)降低，但对复制叉崩溃后RPA2-P没有明显影响。重要的是，我们发现BRCA1促进RAD51的招募和由复制叉停滞诱导的姐妹染色单体交换，而不依赖ATR。相反，当ATR耗尽时，BRCA1耗尽导致RAD51招募和复制叉崩溃引起的姐妹染色单体交换更深刻的缺陷。我们得出结论，BRCA1在复制分叉停滞和崩溃时两种不同的HR介导的修复中起双重作用。我们的数据为观察到BRCA1缺陷导致对导致复制障碍的药物高度敏感而与DSB无关的观察奠定了分子基础，并暗示了一种新的机制，即细胞周期检查点的丢失通过增强BRCA1缺陷导致的HR缺陷来促进BRCA1相关肿瘤的发生。
Homologous recombination (HR) is a major mechanism utilized to repair blockage of DNA replication forks. Here, we report that a sister chromatid exchange (SCE) generated by crossover-associated HR efficiently occurs in response to replication fork stalling before any measurable DNA double-strand breaks (DSBs). Interestingly, SCE produced by replication fork collapse following DNA DSBs creation is specifically suppressed by ATR, a central regulator of the replication checkpoint. BRCA1 depletion leads to decreased RPA2 phosphorylation (RPA2-P) following replication fork stalling but has no obvious effect on RPA2-P following replication fork collapse. Importantly, we found that BRCA1 promotes RAD51 recruitment and SCE induced by replication fork stalling independent of ATR. In contrast, BRCA1 depletion leads to a more profound defect in RAD51 recruitment and SCE induced by replication fork collapse when ATR is depleted. We concluded that BRCA1 plays a dual role in two distinct HR-mediated repair upon replication fork stalling and collapse. Our data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and also implicate a novel mechanism by which loss of cell cycle checkpoints promotes BRCA1-associated tumorigenesis via enhancing HR defect resulting from BRCA1 deficiency.
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影响因子：
16
作者：
Berdichevsky, A;Izhar, L;Livneh, Z
通讯作者：
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影响因子：
16.8
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通讯作者：
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