A sophisticated mechanism governs Pol ζ activity in response to replication stress

Chun Li, Shuchen Fan, Pan Li, Yuzhen Bai, Ye Wang, Yueyun Cui, Mengdi Li, Ruru Wang, Yuan Shao, Yingying Wang, Shuo Zheng, Rong Wang, Lijun Gao, Miaomiao Li, Yuanyuan Zheng, Fengting Wang, Sihang Gao, Shiguo Feng, Jianing Wang, Xinqi Qu and Xialu Li ()
Additional contact information
Chun Li: Capital Normal University
Shuchen Fan: Capital Normal University
Pan Li: Capital Normal University
Yuzhen Bai: Capital Normal University
Ye Wang: Capital Normal University
Yueyun Cui: Capital Normal University
Mengdi Li: Capital Normal University
Ruru Wang: Capital Normal University
Yuan Shao: Capital Normal University
Yingying Wang: Capital Normal University
Shuo Zheng: Capital Normal University
Rong Wang: Capital Normal University
Lijun Gao: Capital Normal University
Miaomiao Li: Capital Normal University
Yuanyuan Zheng: Capital Normal University
Fengting Wang: Capital Normal University
Sihang Gao: Capital Normal University
Shiguo Feng: Capital Normal University
Jianing Wang: Capital Normal University
Xinqi Qu: Capital Normal University
Xialu Li: Capital Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract DNA polymerase ζ (Pol ζ) plays an essential role in replicating damaged DNA templates but contributes to mutagenesis due to its low fidelity. Therefore, ensuring tight control of Pol ζ’s activity is critical for continuous and accurate DNA replication, yet the specific mechanisms remain unclear. This study reveals a regulation mechanism of Pol ζ activity in human cells. Under normal conditions, an autoinhibition mechanism keeps the catalytic subunit, REV3L, inactive. Upon encountering replication stress, however, ATR-mediated phosphorylation of REV3L’s S279 cluster activates REV3L and triggers its degradation via a caspase-mediated pathway. This regulation confines the activity of Pol ζ, balancing its essential role against its mutations causing potential during replication stress. Overall, our findings elucidate a control scheme that fine tunes the low-fidelity polymerase activity of Pol ζ under challenging replication scenarios.

Date: 2024
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DOI: 10.1038/s41467-024-52112-z

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