链间交联复制叉近侧结构重排依赖于 ATR、FANCM 和 FANCD2。
Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2.
机构信息
Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, China.
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
出版信息
Cell Rep. 2019 May 7;27(6):1794-1808.e5. doi: 10.1016/j.celrep.2019.04.032.
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.
真核复制体由微型染色体维持（MCM[M]）解旋酶复合物驱动，该复合物围绕模板形成错位环，由 CDC45（C）和 GINS（G）蛋白进行前导链合成。尽管 CDC45-MCM-GINS（CMG）结构表明链间交联（ICLs）绝对阻止复制体，但最近的研究表明，细胞可以在 ICL 初始结合位点的远端重新启动 DNA 合成。在这里，我们报告说，重新启动需要 ATR，并由 FANCD2 和磷酸化的 FANCM 促进。在引入基因组 ICL 后，ATR 和 FANCD2 依赖于 ATR 和 FANCD2，但不依赖于范可尼贫血核心蛋白或 FAAP24，FANCM 结合复制体复合物，同时释放 GINS 蛋白。在 ICL 附近的复制体的原位分析证实了 ATR 依赖性的 GINS 蛋白释放，而 CDC45 保留在重构的复制体上。结果表明，CMG 组成对复制应激具有可塑性。
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