Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response.
Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response.
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DOI：
10.18632/oncotarget.5497
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发表时间：
2015-11-10
期刊：
影响因子：
--
通讯作者：
Ying S
中科院分区：
文献类型：
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作者：
Xing M;Wang X;Palmai-Pallag T;Shen H;Helleday T;Hickson ID;Ying S
MUS 81蛋白属于保守的DNA结构特异性核酸酶家族，在DNA复制和修复中发挥重要作用。小鼠中Mus 81基因的失活对胚胎发育没有重大的有害后果，尽管已经报道了癌症易感性。我们已经研究了MUS 81在人类细胞中的作用，通过使用shRNA急性消耗蛋白质。我们发现，从人成纤维细胞中消耗MUS 81导致ssDNA的积累和组成性DNA损伤反应，最终激活细胞衰老。此外，我们表明，MUS 81是所需的有效的复制叉进展在一个不受干扰的S-阶段，并恢复生产复制后，复制失速。这些结果证明了MUS 81核酸酶在维持复制叉完整性中的重要作用。
The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81 is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity.