Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery.
Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery.
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DOI：
10.7554/elife.41426
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发表时间：
2018-11-13
期刊：
影响因子：
7.7
通讯作者：
Huang TT
中科院分区：
文献类型：
--
作者：
Tonzi P;Yin Y;Lee CWT;Rothenberg E;Huang TT
DNA复制应激的定义通常是复制分叉进程的减慢或停滞，导致局部或全局DNA合成抑制。不能及时解决复制应激会导致细胞周期缺陷、基因组不稳定和人类疾病；然而，分叉恢复的机制仍然不清楚。在这里，我们证明了跨损伤DNA聚合酶(Pol)kappa，一种DinB同源物，在核苷酸剥夺条件下保护和重新启动停滞的复制叉子方面具有独特的作用。重要的是，在依赖羟基脲(HU)的叉状重启过程中，Pol kappa介导的DNA合成受到Fanconi贫血(FA)途径和增殖细胞核抗原多泛素化的调节。Pol kappa的丢失阻止了对停滞不前的复制叉的及时修复，导致复制相关的基因组不稳定，以及依赖于p53的细胞周期缺陷。综上所述，我们的结果确定了Pol kappa在促进停滞叉子部位的DNA合成和复制应激恢复方面以前没有预料到的作用。
DNA replication stress is often defined by the slowing or stalling of replication fork progression leading to local or global DNA synthesis inhibition. Failure to resolve replication stress in a timely manner contribute toward cell cycle defects, genome instability and human disease; however, the mechanism for fork recovery remains poorly defined. Here, we show that the translesion DNA polymerase (Pol) kappa, a DinB orthologue, has a unique role in both protecting and restarting stalled replication forks under conditions of nucleotide deprivation. Importantly, Pol kappa-mediated DNA synthesis during hydroxyurea (HU)-dependent fork restart is regulated by both the Fanconi Anemia (FA) pathway and PCNA polyubiquitination. Loss of Pol kappa prevents timely rescue of stalled replication forks, leading to replication-associated genomic instability, and a p53-dependent cell cycle defect. Taken together, our results identify a previously unanticipated role for Pol kappa in promoting DNA synthesis and replication stress recovery at sites of stalled forks.