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Peer-reviewedCC BY 4.0The EMBO Journal

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

  • Juan de Dios Barba Tena1,2
  • Riccardo Montecchi1
  • Maxime Lambert1,3
  • Thomas Defrance1,4
  • Elisabeth Gueydon1
  • Julie Petit1
  • Marjorie Drac4
  • Noémie Legoff1
  • Michela Galli1
  • Isabelle Goiffon1
  • Thierry Gostan5
  • Khadija El Koulali6
4 more authors
  • Serge Urbach7
  • David Toczyski8
  • Nicolas Talarek1
  • Etienne Schwob1
8 affiliations
  1. 1IGMM, CNRS, Univ Montpellier, Montpellier, France
  2. 2Present Address: Dortmund Life Science Center, TU Dortmund, Dortmund, Germany
  3. 3Present Address: IDgenX, Montpellier, France
  4. 4MDC, BioCampus, IGMM, CNRS, Univ Montpellier, Montpellier, France
  5. 5SERANAD, IGMM, CNRS, Univ Montpellier, Montpellier, France
  6. 6BCM, Univ. Montpellier, CNRS, INSERM, Montpellier, France
  7. 7IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France
  8. 8Dept Biochemistry & Biophysics, UCSF, San Francisco, CA USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{tena2026switch,
  title = {{Switch from canonical to recombination-dependent DNA synthesis by M-CDK phosphorylation of DNA Polα}},
  author = {Juan de Dios Barba Tena and Riccardo Montecchi and Maxime Lambert and Thomas Defrance and Elisabeth Gueydon and Julie Petit and Marjorie Drac and Noémie Legoff and Michela Galli and Isabelle Goiffon and Thierry Gostan and Khadija El Koulali and Serge Urbach and David Toczyski and Nicolas Talarek and Etienne Schwob},
  journal = {The EMBO Journal},
  year = {2026},
  month = oct,
  doi = {10.1038/s44318-026-00919-5},
  url = {https://hal.science/hal-05803552v1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Switch from canonical to recombination-dependent DNA synthesis by M-CDK phosphorylation of DNA Polα
AU  - Juan de Dios Barba Tena
AU  - Riccardo Montecchi
AU  - Maxime Lambert
AU  - Thomas Defrance
AU  - Elisabeth Gueydon
AU  - Julie Petit
AU  - Marjorie Drac
AU  - Noémie Legoff
AU  - Michela Galli
AU  - Isabelle Goiffon
AU  - Thierry Gostan
AU  - Khadija El Koulali
AU  - Serge Urbach
AU  - David Toczyski
AU  - Nicolas Talarek
AU  - Etienne Schwob
PY  - 2026
DA  - 2026/10/10
JO  - The EMBO Journal
DO  - 10.1038/s44318-026-00919-5
UR  - https://hal.science/hal-05803552v1
AB  - 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.
SN  - 0261-4189
SN  - 1460-2075
ER  -