ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links.
ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links.
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DOI：
10.1016/j.celrep.2018.08.019
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发表时间：
2018-09-04
期刊：
影响因子：
8.8
通讯作者：
Lopes M
中科院分区：
文献类型：
--
作者：
Mutreja K;Krietsch J;Hess J;Ursich S;Berti M;Roessler FK;Zellweger R;Patra M;Gasser G;Lopes M
链间交联（ICLs）是由广泛使用的抗癌药物引起的干扰DNA代谢的毒性DNA病变。长期以来，它们一直被认为是复制分叉的绝对障碍，暗示了在停滞或聚合的复制分叉中复杂的DNA修复过程。最近的证据挑战了这一观点，提出单分叉通过尚难以捉摸的机制穿越ICLs。结合人类细胞中的ICL免疫标记和单分子方法，我们现在发现ICL诱导导致全局复制分叉减慢，包括未被ICL直接挑战的分叉。主动分叉减慢与RAD51复制染色质的快速募集和RAD51/ zranb3介导的分叉逆转有关。这种分叉速度和结构的全局调节需要ATR激活，促进单分叉ICL穿越-这里，通过电子显微镜直接可见-并防止不及时的ICL处理导致染色体断裂。我们建议通过重塑来减缓整体的叉子，为模板修复提供了更多的时间，并促进了残余病变的旁路，限制了叉子相关的处理。在没有直接受到ICL挑战的分叉上也观察到分叉减慢和逆转，分叉逆转有助于ICL的穿越并限制与ICL解钩相关的dsb， ICL的穿越可以通过电子显微镜在人类细胞中直接观察到，ATR介导不同基因毒性治疗下的全局分叉减慢和逆转，DNA链间交联（ICL）的复制偶联修复促进对化疗治疗的抗性。Mutreja等人通过观察单个病变和复制中间体报道，分叉在icl处和远离病变处减慢并逆转。这种atr介导的反应有助于复制过程中的病变旁路，并限制叉相关加工的染色体断裂。
Interstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent evidence challenged this view, proposing that single forks traverse ICLs by yet elusive mechanisms. Combining ICL immunolabeling and single-molecule approaches in human cells, we now show that ICL induction leads to global replication fork slowing, involving forks not directly challenged by ICLs. Active fork slowing is linked to rapid recruitment of RAD51 to replicating chromatin and to RAD51/ZRANB3-mediated fork reversal. This global modulation of fork speed and architecture requires ATR activation, promotes single-fork ICL traverse—here, directly visualized by electron microscopy—and prevents chromosomal breakage by untimely ICL processing. We propose that global fork slowing by remodeling provides more time for template repair and promotes bypass of residual lesions, limiting fork-associated processing. Fork slowing and reversal are also observed at forks not directly challenged by ICLs Fork reversal assists ICL traverse and limits DSBs associated with ICL unhooking ICL traverse can be directly visualized in human cells by electron microscopy ATR mediates global fork slowing and reversal upon different genotoxic treatments Replication-coupled repair of DNA interstrand cross-links (ICLs) promotes resistance to chemotherapeutic treatments. Visualizing individual lesions and replication intermediates, Mutreja et al. report that forks slow down and reverse both at ICLs and away from lesions. This ATR-mediated response assists lesion bypass during replication and limits chromosomal breakage by fork-associated processing.
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