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Replication fork plasticity upon replication stress requires rapid nuclear actin polymerization

Palumbieri, M. D.; Merigliano, C.; Gonzalez-Acosta, D.; von Kaenel, T.; Welter, B.; Stoy, H.; Krietsch, J.; Ulferts, S.; Sanchi, A.; Grosse, R.; Chiolo, I.; Lopes, M.

2023-03-25 cancer biology
10.1101/2023.03.24.534097 bioRxiv
Show 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, rapidly extending in number and thickness upon genotoxic treatments, and taking frequent 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 plasticity is linked to reduced recruitment of RAD51 and SMARCAL1 to nascent DNA. Conversely, PRIMPOL gains access to replicating chromatin, promoting unrestrained and discontinuous DNA synthesis, which is associated with increased chromosomal instability and decreased cellular resistance to replication stress. Hence, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.

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