1. A sophisticated mechanism governs Pol ζ activity in response to replication stress
- Author
-
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
- Subjects
Science - 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.
- Published
- 2024
- Full Text
- View/download PDF