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Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity

Author

Listed:
  • Maria Dilia Palumbieri

    (University of Zurich)

  • Chiara Merigliano

    (University of Southern California)

  • Daniel González-Acosta

    (University of Zurich)

  • Danina Kuster

    (University of Zurich)

  • Jana Krietsch

    (University of Zurich)

  • Henriette Stoy

    (University of Zurich
    Copenhagen University)

  • Thomas Känel

    (University of Zurich)

  • Svenja Ulferts

    (Medical Faculty, University of Freiburg)

  • Bettina Welter

    (University of Zurich)

  • Joël Frey

    (University of Zurich)

  • Cyril Doerdelmann

    (University of Zurich)

  • Andrea Sanchi

    (University of Zurich)

  • Robert Grosse

    (Medical Faculty, University of Freiburg
    University of Freiburg)

  • Irene Chiolo

    (University of Southern California)

  • Massimo Lopes

    (University of Zurich)

Abstract

Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.

Suggested Citation

  • Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43183-5
    DOI: 10.1038/s41467-023-43183-5
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