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

Author

Listed:
  • Chun Li

    (Capital Normal University)

  • Shuchen Fan

    (Capital Normal University)

  • Pan Li

    (Capital Normal University)

  • Yuzhen Bai

    (Capital Normal University)

  • Ye Wang

    (Capital Normal University)

  • Yueyun Cui

    (Capital Normal University)

  • Mengdi Li

    (Capital Normal University)

  • Ruru Wang

    (Capital Normal University)

  • Yuan Shao

    (Capital Normal University)

  • Yingying Wang

    (Capital Normal University)

  • Shuo Zheng

    (Capital Normal University)

  • Rong Wang

    (Capital Normal University)

  • Lijun Gao

    (Capital Normal University)

  • Miaomiao Li

    (Capital Normal University)

  • Yuanyuan Zheng

    (Capital Normal University)

  • Fengting Wang

    (Capital Normal University)

  • Sihang Gao

    (Capital Normal University)

  • Shiguo Feng

    (Capital Normal University)

  • Jianing Wang

    (Capital Normal University)

  • Xinqi Qu

    (Capital Normal University)

  • Xialu Li

    (Capital Normal University)

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.

Suggested Citation

  • 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 Wa, 2024. "A sophisticated mechanism governs Pol ζ activity in response to replication stress," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52112-z
    DOI: 10.1038/s41467-024-52112-z
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    References listed on IDEAS

    as
    1. Inés Paniagua & Zainab Tayeh & Mattia Falcone & Santiago Hernández Pérez & Aurora Cerutti & Jacqueline J. L. Jacobs, 2022. "MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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