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

Maria Dilia Palumbieri, Chiara Merigliano, Daniel González-Acosta, Danina Kuster, Jana Krietsch, Henriette Stoy, Thomas Känel, Svenja Ulferts, Bettina Welter, Joël Frey, Cyril Doerdelmann, Andrea Sanchi, Robert Grosse, Irene Chiolo () and Massimo Lopes ()
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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
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
Irene Chiolo: University of Southern California
Massimo Lopes: University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43183-5

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