RNF4 Controls the Extent of Replication Fork Reversal to Preserve Genome Stability

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 May 31

PMID 35640614

Authors

Linli Ding

Yi Luo

Tian Tian

Xu Chen

Yulan Yang

Min Bu

Jinhua Han

Bing Yang

Haiyan Yan

Ting Liu

Mengjie Wu

Guofei Zhang

Yipeng Xu

Shaoxing Zhu

Michael S Y Huen

Genxiang Mao

Jun Huang

Affiliations

Soon will be listed here.

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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