Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells

Wei Wu (), Szymon A. Barwacz, Rahul Bhowmick, Katrine Lundgaard, Marisa M. Gonçalves Dinis, Malgorzata Clausen, Masato T. Kanemaki and Ying Liu ()
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Wei Wu: University of Copenhagen
Szymon A. Barwacz: University of Copenhagen
Rahul Bhowmick: University of Copenhagen
Katrine Lundgaard: University of Copenhagen
Marisa M. Gonçalves Dinis: University of Copenhagen
Malgorzata Clausen: University of Copenhagen
Masato T. Kanemaki: National Institute of Genetics, Research Organization of Information and Systems (ROIS)
Ying Liu: University of Copenhagen

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Oncogene activation creates DNA replication stress (RS) in cancer cells, which can generate under-replicated DNA regions (UDRs) that persist until cells enter mitosis. UDRs also have the potential to generate DNA bridges in anaphase cells or micronuclei in the daughter cells, which could promote genomic instability. To suppress such damaging changes to the genome, human cells have developed a strategy to conduct ‘unscheduled’ DNA synthesis in mitosis (termed MiDAS) that serves to rescue under-replicated loci. Previous studies have shown that MiDAS proceeds via a POLD3-dependent pathway that shows some features of break-induced replication. Here, we define how human cells utilize both DNA gap filling (REV1 and Pol ζ) and replicative (Pol δ) DNA polymerases to complete genome duplication following a perturbed S-phase. We present evidence for the existence of a polymerase-switch during MiDAS that is required for new DNA synthesis at UDRs. Moreover, we reveal that, upon oncogene activation, cancer cell survival is significantly compromised when REV1 is depleted, suggesting that REV1 inhibition might be a feasible approach for the treatment of some human cancers.

Date: 2023
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DOI: 10.1038/s41467-023-35992-5

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