Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, 100048, China.
Nat Commun. 2024 Aug 31;15(1):7562. doi: 10.1038/s41467-024-52112-z.
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.
DNA 聚合酶 ζ（Pol ζ）在复制受损的 DNA 模板方面发挥着重要作用，但由于其低保真度，也会导致突变。因此，确保 Pol ζ 活性的严格控制对于连续和准确的 DNA 复制至关重要，但具体的机制仍不清楚。本研究揭示了人细胞中 Pol ζ 活性的调节机制。在正常情况下，自动抑制机制使催化亚基 REV3L 处于非活性状态。然而，在遇到复制应激时，ATR 介导的 REV3L 的 S279 簇磷酸化激活 REV3L，并通过半胱天冬酶介导的途径触发其降解。这种调节限制了 Pol ζ 的活性，在复制应激期间平衡了其作为潜在诱变因子的基本作用。总的来说，我们的发现阐明了一种控制方案，即在具有挑战性的复制情况下精细调节 Pol ζ 的低保真度聚合酶活性。
