Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells
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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.
Originalsprog | Engelsk |
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Artikelnummer | 706 |
Tidsskrift | Nature Communications |
Vol/bind | 14 |
Udgave nummer | 1 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Ian D. Hickson for inspiring discussions and critical reading of the manuscript. Wei Wu was supported by the Chinese National Natural Science Foundation (82103232; W.W.). The work in the Liu laboratory is supported by the European Union (H2020/Marie Skłodowska-Curie Actions; 859853; Y.L.), Danish Independent Research Fund (1030-00180B; Y. L.), and Danish National Research Foundation (DNRF115; Y.L.). The work in the Kanemaki laboratory is supported by the JSPS KAKENHI grants (20H05396 and 21H04719; M.T.K.).
Publisher Copyright:
© 2023, The Author(s).
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