RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress.
RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress.
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DOI：
10.1038/onc.2015.427
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发表时间：
2016-07-28
期刊：
影响因子：
8
通讯作者：
Behrens A
中科院分区：
文献类型：
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作者：
Kanu N;Zhang T;Burrell RA;Chakraborty A;Cronshaw J;DaCosta C;Grönroos E;Pemberton HN;Anderton E;Gonzalez L;Sabbioneda S;Ulrich HD;Swanton C;Behrens A
DNA复制机制总是遇到障碍，减缓复制叉的进展，并威胁到完全复制和姐妹染色单体的忠实分离。由此产生的复制应激激活ATR，ATR是参与解决受损DNA复制的主要激酶。此外，复制应激还激活相关激酶ATM，这是防止有丝分裂分离错误所必需的。然而，ATM激活复制应力的分子机制尚未确定。在这里，我们表明，monoubiquitinated增殖细胞核抗原（PCNA），停滞的复制叉的标志物，通过WRN相互作用蛋白1（WRNIP 1）与ATM辅因子ATMIN相互作用。ATMIN、WRNIP 1和RAD 18（负责PCNA单泛素化的E3连接酶）是ATM信号传导和由复制应激诱导的53 BP 1病灶形成所特别需要的，而不是电离辐射。因此，WRNIP 1将PCNA单泛素化与ATMIN/ATM连接起来，以响应复制应激激活ATM信号传导，并有助于维持基因组稳定性。
The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability.