2. Academic Validation
  3. 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

  • Mol Cell. 2021 Jan 7;81(1):198-211.e6. doi: 10.1016/j.molcel.2020.11.007.
Tian Tian 1,  Min Bu 1,  Xu Chen 1,  Linli Ding 1,  Yulan Yang 1,  Jinhua Han 1,  Xin-Hua Feng 1,  Pinglong Xu 1,  Ting Liu 2,  Songmin Ying 3,  Yang Lei 4,  Qing Li 4,  Jun Huang 5
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 2 Department of Cell Biology and Department of General Surgery of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 3 Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 4 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 5 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: jhuang@zju.edu.cn.
PMID: 33296677 DOI: 10.1016/j.molcel.2020.11.007
Abstract

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.

Keywords

DNA topoisomerase; DNA translocase; SUMO E3 ligase; SUMOylation; genome instability; replication fork restart; replication fork reversal.

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