LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.
LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.
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DOI：
10.1083/jcb.202009147
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发表时间：
2021-08-02
期刊：
影响因子：
--
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Fan Y;Köberlin MS;Ratnayeke N;Liu C;Deshpande M;Gerhardt J;Meyer T
Fan等人表明，S期期间的复制体解体是有效DNA复制所需的，其通过在染色质结合区室和可溶区室之间再循环基本复制体组分来实现。在两个会聚的DNA复制叉相遇后，活性复制体被分解并从染色质上卸载。复制体解体的一个关键过程是CMG解旋酶（CDC 45-MCM-GINS）的卸载，其在秀丽隐杆线虫和非洲爪蟾中由E3泛素连接酶CRL 2LRR 1启动。在这里，我们表明，缺乏LRR 1的人类细胞无法卸载CMG解旋酶和积累越来越多的染色质结合的复制体成分的细胞进展通过S期。显著地，我们证明，未能拆卸复制体减少DNA复制的速率越来越多地在整个S期通过隔离限速复制体组件染色质和阻止其回收。CMG解旋酶在G2期与染色质的持续结合通过激活ATR介导的G2/M检查点来阻断有丝分裂。最后，我们提供的证据表明，LRR 1是人类细胞分裂的必需基因，这表明，CRL 2LRR 1酶活性是癌细胞增殖所必需的，因此是癌症治疗的潜在靶点。
Fan et al. show that replisome disassembly during S phase is required for efficient DNA replication by recycling essential replisome components between chromatin-bound and soluble compartments. After two converging DNA replication forks meet, active replisomes are disassembled and unloaded from chromatin. A key process in replisome disassembly is the unloading of CMG helicases (CDC45–MCM–GINS), which is initiated in Caenorhabditis elegans and Xenopus laevis by the E3 ubiquitin ligase CRL2LRR1. Here, we show that human cells lacking LRR1 fail to unload CMG helicases and accumulate increasing amounts of chromatin-bound replisome components as cells progress through S phase. Markedly, we demonstrate that the failure to disassemble replisomes reduces the rate of DNA replication increasingly throughout S phase by sequestering rate-limiting replisome components on chromatin and blocking their recycling. Continued binding of CMG helicases to chromatin during G2 phase blocks mitosis by activating an ATR-mediated G2/M checkpoint. Finally, we provide evidence that LRR1 is an essential gene for human cell division, suggesting that CRL2LRR1 enzyme activity is required for the proliferation of cancer cells and is thus a potential target for cancer therapy.
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