Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway.
Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway.
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DOI：
10.1083/jcb.200803173
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发表时间：
2008-10-20
期刊：
影响因子：
--
通讯作者：
Pichierri P
中科院分区：
文献类型：
--
作者：
Franchitto A;Pirzio LM;Prosperi E;Sapora O;Bignami M;Pichierri P
如果不能稳定和适当地处理停滞的复制叉，就会导致染色体不稳定，这是癌细胞和几种以癌症易感性为特征的人类遗传疾病的标志。WRN是一种在癌症易发疾病Werner综合征(WS)中突变的RecQ样酶，丢失WRN会导致双链断裂(DSB)快速积累，并在DNA复制停止时从染色质中去除增殖细胞核抗原。WRN缺陷细胞中MUS81内切酶的敲除完全防止了叉子失速后DSB的积累。此外，WS细胞中的MUS81基因敲除导致重组酶染色质募集减少，姐妹染色单体交换的产量减少，复制停止后存活率降低。因此，我们提供了新的证据，证明WRN是为了避免DSB的积累和复制扰动后的叉子崩溃，并且在这种病理条件下，迅速产生依赖于MUS81的DSB有助于从羟基脲介导的复制抑制中恢复过来。
Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.
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