Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis

Camille Gelot, Marton Tibor Kovacs, Simona Miron, Emilie Mylne, Alexis Haan, Liza Boeffard-Dosierre, Rania Ghouil, Tatiana Popova, Florent Dingli, Damarys Loew, Josée Guirouilh-Barbat, Elaine Nery, Sophie Zinn-Justin and Raphael Ceccaldi ()
Additional contact information
Camille Gelot: INSERM U830, PSL Research University, Institut Curie
Marton Tibor Kovacs: INSERM U830, PSL Research University, Institut Curie
Simona Miron: CEA, CNRS, Paris-Saclay University
Emilie Mylne: INSERM U830, PSL Research University, Institut Curie
Alexis Haan: INSERM U830, PSL Research University, Institut Curie
Liza Boeffard-Dosierre: CEA, CNRS, Paris-Saclay University
Rania Ghouil: CEA, CNRS, Paris-Saclay University
Tatiana Popova: PSL Research University, Institut Curie
Florent Dingli: PSL Research University
Damarys Loew: PSL Research University
Josée Guirouilh-Barbat: Université de Paris, INSERM U1016, UMR 8104 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Cochin
Elaine Nery: PSL Research University, Institut Curie
Sophie Zinn-Justin: CEA, CNRS, Paris-Saclay University
Raphael Ceccaldi: INSERM U830, PSL Research University, Institut Curie

Nature, 2023, vol. 621, issue 7978, 415-422

Abstract: Abstract DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3–5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.

Date: 2023
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DOI: 10.1038/s41586-023-06506-6

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