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

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-30
DOI
https://doi.org/10.1038/s41467-024-52112-z
Citations
5
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.94

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article

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

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Nature Communications
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article

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

Jianing Wang, Yuzhen Bai, Xialu Li, Sihang Gao, Yuanyuan Zheng, Shiguo Feng, Fengting Wang, Ruru Wang, Rong Wang, Yingying Wang, Ye Wang, Pan Li, Miaomiao Li, Mengdi Li, Yuan Shao, Lijun Gao, Shuo Zheng, Chun Li, Xinqi Qu, Yueyun Cui, Shengtao Fan
article en
5 citations

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.

Nature CommunicationsVol. 15(1)
Beijing Normal University (CN), Capital Normal University (CN)
National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, Tsinghua University
Openalex Percentile: Top 25%
RNA Research and Splicing
0.94
DOIOpen Access PDFOpenAlex
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