Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2
Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2
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链间交联近端复制体的重塑依赖于 ATR、FANCM 和 FANCD2
DOI：
10.1016/j.celrep.2019.04.032
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发表时间：
2019-05-07
期刊：
影响因子：
8.8
通讯作者：
Seidman, Michael M.
中科院分区：
文献类型：
--
作者：
Huang, Jing;Zhang, Jing;Seidman, Michael M.
真核复制体是由微小染色体维持(MCM[M])解旋酶复合体驱动的，解旋酶复合体是一个围绕在模板周围的偏移环，由CDC45(C)和gins(G)蛋白合成先导链。虽然CDC45 MCM gins(CMG)结构暗示链间交联(ICL)是复制体的绝对障碍，但最近的研究表明，细胞可以在最初相遇远端的ICL一侧重新开始DNA合成。在这里，我们报告了RESTART需要ATR，并被FANCD2和磷酸化的FANCM促进。随着基因组ICL的引入，FANCM依赖于ATR和FANCD2，而不依赖于Fanconi贫血核心蛋白或FAAP24，结合复制体复合体，伴随着gins蛋白的释放。对ICL附近复制体的原位分析证实，GINS蛋白的释放依赖于ATR，而CDC45保留在重塑的复制体上。结果表明，CMG组分对复制应力的响应具有可塑性。
Eukaryotic replisomes are driven by the mini chromosome maintenance (MCM [M]) helicase complex, an offset ring locked around the template for leading strand synthesis by CDC45 (C) and GINS (G) proteins. Although the CDC45 MCM GINS (CMG) structure implies that interstrand crosslinks (ICLs) are absolute blocks to replisomes, recent studies indicate that cells can restart DNA synthesis on the side of the ICL distal to the initial encounter. Here, we report that restart requires ATR and is promoted by FANCD2 and phosphorylated FANCM. Following introduction of genomic ICLs and dependent on ATR and FANCD2 but not on the Fanconi anemia core proteins or FAAP24, FANCM binds the replisome complex, with concomitant release of the GINS proteins. In situ analysis of replisomes proximal to ICLs confirms the ATR-dependent release of GINS proteins while CDC45 is retained on the remodeled replisome. The results demonstrate the plasticity of CMG composition in response to replication stress.