CARM1 regulates replication fork speed and stress response by stimulating PARP1.
CARM1 regulates replication fork speed and stress response by stimulating PARP1.
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DOI：
10.1016/j.molcel.2020.12.010
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发表时间：
2021-02-18
期刊：
影响因子：
16
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Genois MM;Gagné JP;Yasuhara T;Jackson J;Saxena S;Langelier MF;Ahel I;Bedford MT;Pascal JM;Vindigni A;Poirier GG;Zou L
DNA复制叉使用多种机制来处理复制压力，但如何选择机制仍然知之甚少。在这里，我们表明，CARM1与复制叉和减少叉速度独立于其甲基转移酶活性。CARM1缺陷细胞中复制叉的加速需要RECQ1和RAD18，RECQ1解决反向叉，RAD18促进跨损伤合成。CARM 1的缺失减少了叉逆转，增加了单链DNA缺口，但允许细胞耐受更高的复制应激。在机制上，CARM1与PARP1相互作用并促进复制叉处的PAR化。在体外，CARM1通过增强其DNA结合来刺激PARP1活性，并与HPF1联合作用以激活PARP1。因此，通过刺激PARP1，CARM1减慢复制叉并促进在应激反应中使用叉逆转，揭示了CARM1和PARP1在叉处作为调节模块来控制叉速度和应激反应机制的选择。Genois等人（2020）发现CARM1在DNA复制叉上具有甲基转移酶非依赖性功能，以控制叉速度和应激反应机制的选择。通过促进PARP 1激活，CARM1有利于叉逆转，而不是使用PrimPol和translesion合成，减缓复制叉并保持复制保真度。
DNA replication forks use multiple mechanisms to deal with replication stress, but how the choice of mechanisms is made is still poorly understood. Here, we show that CARM1 associates with replication forks and reduces fork speed independently of its methyltransferase activity. The speeding of replication forks in CARM1-deficient cells requires RECQ1, which resolves reversed forks, and RAD18, which promotes translesion synthesis. Loss of CARM1 reduces fork reversal, increases single-stranded DNA gaps, but allows cells to tolerate higher replication stress. Mechanistically, CARM1 interacts with PARP1 and promotes PARylation at replication forks. In vitro, CARM1 stimulates PARP1 activity by enhancing its DNA binding and acts jointly with HPF1 to activate PARP1. Thus, by stimulating PARP1, CARM1 slows replication forks and promotes the use of fork reversal in stress response, revealing that CARM1 and PARP1 function as a regulatory module at forks to control fork speed and the choice of stress response mechanisms. Genois et al. (2020) find that CARM1 has a methyltransferase-independent function at DNA replication forks to control fork speed and the choice of stress response mechanisms. By promoting PARP1 activation, CARM1 favors fork reversal over the use of PrimPol and translesion synthesis, slowing replication forks and maintaining replication fidelity.
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影响因子：
16
作者：
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