Switch from canonical to recombination-dependent DNA synthesis by M-CDK phosphorylation of DNA Polα

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Cells preserve genome stability while occasionally generating genetic diversity through mutations and chromosomal rearrangements, but how these opposing outcomes are balanced remains unclear. Because late-replicating regions evolve more rapidly, we investigated the consequences of reduced origin licensing and lengthened S phase in yeast. Under these conditions, cells progress slowly through S phase without checkpoint activation, and enter mitosis with under-replicated DNA. We show that mitotic cyclin-dependent kinase (M-CDK) phosphorylates DNA polymerase α (Pol α), displacing it from replication forks and triggering fork collapse at mitotic entry. The resulting DNA damage response provides a window for mitotic DNA synthesis (MiDAS), enabling completion of replication through error-prone, recombination-dependent mechanisms resembling break-induced replication (BIR) and Fork Stalling & Template Switching (FoSTeS). These findings identify Pol α as a critical M-CDK target that promotes the transition from canonical replication to recombination-driven DNA synthesis when cells enter mitosis with incompletely-duplicated chromosomes. This mechanism offers a potential explanation for the accelerated evolution of late-replicating genomic regions.
Funding Information
  • Agence Nationale de la Recherche (CE12-18-0018)
  • Fondation ARC pour la Recherche sur le Cancer (PJA 20151203349)
  • Biocampus Montpellier (R&D 2022)
  • Region Occitanie FEDER (PRRI PFS-Bio)
  • Institut de Genetique Moleculaire de Montpellier (Core funding)

This publication has 103 references indexed in Scilit: