CUL-2(LRR-1) and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.
CUL-2(LRR-1) and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.
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DOI：
10.1038/ncb3500
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发表时间：
2017-05
影响因子：
21.3
通讯作者：
Labib K
中科院分区：
文献类型：
--
作者：
Sonneville R;Moreno SP;Knebel A;Johnson C;Hastie CJ;Gartner A;Gambus A;Labib K
复制体分解是真核生物 DNA 复制的最后一步，涉及 CMG 解旋酶 (Cdc45-MCM-GINS) 的泛素化和 CDC48 依赖性溶解。使用秀丽隐杆线虫早期胚胎和非洲爪蟾卵提取物，我们发现 E3 连接酶 CUL-2LRR-1 与复制体结合，并与 CDC-48 辅因子 UFD-1 和 NPL-4 一起驱动 CMG 的泛素化和分解。从青蛙卵提取物的染色质中去除 CMG 需要 CUL2 neddylation，我们的数据表明 CUL2LRR1 的染色质募集是 DNA 复制终止过程中的关键调节步骤。然而有趣的是，CMG 在缺乏 CUL-2LRR-1 的线虫中持续存在于染色质上，直到前期，但随后被需要 CDC-48 辅助因子 UBXN-3（与人类肿瘤抑制因子 FAF1 直系同源）的有丝分裂途径去除。 lrr-1 和 ubxn-3 的部分失活会导致合成致死，这表明未来可以通过更深入地了解后生动物中的 CMG 分解来进行治疗。
Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (Cdc45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus egg extracts, we show that the E3 ligase CUL-2LRR-1 associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 co-factors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2LRR1 as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2LRR-1, but is then removed by a mitotic pathway that requires the CDC-48 co-factor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically.