2. Academic Validation
  3. RNF4 controls the extent of replication fork reversal to preserve genome stability

RNF4 controls the extent of replication fork reversal to preserve genome stability

  • Nucleic Acids Res. 2022 Jun 10;50(10):5672-5687. doi: 10.1093/nar/gkac447.
Linli Ding 1,  Yi Luo 1,  Tian Tian 2,  Xu Chen 1,  Yulan Yang 1,  Min Bu 1,  Jinhua Han 1,  Bing Yang 1,  Haiyan Yan 3,  Ting Liu 4,  Mengjie Wu 5,  Guofei Zhang 6,  Yipeng Xu 7,  Shaoxing Zhu 7,  Michael S Y Huen 8,  Genxiang Mao 9,  Jun Huang 9 10
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, Guangdong, China.
  • 3 School of Medicine, Zhejiang University City of College, Hangzhou 310015, Zhejiang, China.
  • 4 Department of Cell Biology, and Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 5 The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine and Key laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310058, Zhejiang, China.
  • 6 Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 7 Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310058, Zhejiang, China.
  • 8 Department of Anatomy, The University of Hong Kong, Hong Kong, China.
  • 9 Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou 310030, Zhejiang, China.
  • 10 Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China.
PMID: 35640614 DOI: 10.1093/nar/gkac447
Abstract

Replication fork reversal occurs via a two-step process that entails reversal initiation and reversal extension. DNA Topoisomerase IIalpha (TOP2A) facilitates extensive fork reversal, on one hand through resolving the topological stress generated by the initial reversal, on the other hand via its role in recruiting the SUMO-targeted DNA translocase PICH to stalled forks in a manner that is dependent on its SUMOylation by the SUMO E3 ligase ZATT. However, how TOP2A activities at stalled forks are precisely regulated remains poorly understood. Here we show that, upon replication stress, the SUMO-targeted ubiquitin E3 ligase RNF4 accumulates at stalled forks and targets SUMOylated TOP2A for ubiquitination and degradation. Downregulation of RNF4 resulted in aberrant activation of the ZATT-TOP2A-PICH complex at stalled forks, which in turn led to excessive reversal and elevated frequencies of fork collapse. These results uncover a previously unidentified regulatory mechanism that regulates TOP2A activities at stalled forks and thus the extent of fork reversal.

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