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

• Published in: Nature communications Vol. 15; no. 1; pp. 7562 - 16
• Main Authors: Li, Chun, Fan, Shuchen, Li, Pan, Bai, Yuzhen, Wang, Ye, Cui, Yueyun, Li, Mengdi, Wang, Ruru, Shao, Yuan, Wang, Yingying, Zheng, Shuo, Wang, Rong, Gao, Lijun, Li, Miaomiao, Zheng, Yuanyuan, Wang, Fengting, Gao, Sihang, Feng, Shiguo, Wang, Jianing, Qu, Xinqi, Li, Xialu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/51; 14/32; 14/34; 14/63; 38/15; 45/41; 45/77; 49/88; 49/90; 631/337/1427/2354; 631/337/151/2354; Accuracy; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Caspase; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA polymerase; DNA Replication; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Fidelity; HEK293 Cells; Humanities and Social Sciences; Humans; multidisciplinary; Mutagenesis; Phosphorylation; Replication; Science; Science (multidisciplinary); Stress, Physiological
• ISSN: 2041-1723; 2041-1723
• 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 polymerase ζ (Pol ζ) maintains continuity but impairs accuracy during DNA replication. Here, the authors report a mechanism by which human cells precisely control the essential, yet mutagenic, activity of Pol ζ to ensure both continuation and fidelity during DNA replication challenges.