The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability.

Tian Tian, Min Bu, Xu Chen, Linli Ding, Yulan Yang, Jinhua Han, Xin-Hua Feng, Pinglong Xu, Ting Liu, Songmin Ying, Yang Lei, Qing Li, Jun Huang

Molecular cell 2021 Jan 07

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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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Tian Tian, Min Bu, Xu Chen, Linli Ding, Yulan Yang, Jinhua Han, Xin-Hua Feng, Pinglong Xu, Ting Liu, Songmin Ying, Yang Lei, Qing Li, Jun Huang. The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability. Molecular cell. 2021 Jan 07;81(1):198-211.e6