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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-08-31 DOI:10.1038/s41467-024-52112-z

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, Xialu Li

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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.

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一种复杂的机制控制着 Pol ζ 在应对复制压力时的活性

DNA 聚合酶ζ（Pol ζ）在复制受损 DNA 模板的过程中发挥着至关重要的作用，但由于其保真度低，会导致突变。因此，确保对 Pol ζ 活性的严格控制对于持续、准确地复制 DNA 至关重要，但具体机制仍不清楚。这项研究揭示了人类细胞中 Pol ζ 活性的调控机制。在正常情况下，催化亚基REV3L处于不活跃状态。然而，在遇到复制压力时，ATR 介导的 REV3L S279 簇磷酸化会激活 REV3L，并通过树突酶介导的途径触发其降解。这种调控限制了 Pol ζ 的活性，平衡了它的重要作用和在复制压力下导致突变的潜力。总之，我们的研究结果阐明了一种控制方案，它能在具有挑战性的复制情况下微调 Pol ζ 的低保真度聚合酶活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.