The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability
The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability
复制标题
ZATT-TOP2A-PICH 轴驱动广泛的复制叉逆转以促进基因组稳定性
DOI：
10.1016/j.molcel.2020.11.007
复制
发表时间：
2021-01-07
期刊：
影响因子：
16
通讯作者：
Huang, Jun
中科院分区：
文献类型：
--
作者：
Tian, Tian;Bu, Min;Huang, Jun
复制叉逆转是哺乳动物细胞对复制应激的一种全球性反应，但它是如何发生的仍然知之甚少。在这里，我们表明，在复制应力，DNA拓扑异构酶IIalpha（TOP 2A）被招募到失速叉的方式依赖于SNF 2家族DNA移位酶HLTF，ZRANB 3，SMARCAL 1。这伴随着由SUMO E3连接酶ZATT介导的TOP 2A SUMO化的增加，随后是SUMO靶向DNA移位酶PICH的募集。ZATT-TOP 2A-PICH轴的破坏导致部分反向叉的积累和增强的基因组不稳定性。这些结果表明，分叉反转发生通过一个连续的两步过程。首先，HLTF、ZRANB 3和SMARCAL 1启动有限的分叉逆转，在新复制的姐妹染色单体中产生超螺旋应变。其次，TOP 2A通过解决由此产生的拓扑障碍并通过其在招募PICH到停滞分叉中的作用来驱动广泛的分叉逆转。
Replication fork reversal is a global response to replication stress in mammalian cells, but precisely how it occurs remains poorly understood. Here, we show that, upon replication stress, DNA topoisomerase IIalpha (TOP2A) is recruited to stalled forks in a manner dependent on the SNF2-family DNA translocases HLTF, ZRANB3, and SMARCAL1. This is accompanied by an increase in TOP2A SUMOylation mediated by the SUMO E3 ligase ZATT and followed by recruitment of a SUMO-targeted DNA translocase, PICH. Disruption of the ZATT-TOP2A-PICH axis results in accumulation of partially reversed forks and enhanced genome instability. These results suggest that fork reversal occurs via a sequential two-step process. First, HLTF, ZRANB3, and SMARCAL1 initiate limited fork reversal, creating superhelical strain in the newly replicated sister chromatids. Second, TOP2A drives extensive fork reversal by resolving the resulting topological barriers and via its role in recruiting PICH to stalled forks.