Polymerase theta repairs persistent G1-induced DNA breaks in S-phase during class switch recombination

Timea Marton, Jinglong Wang, Amaury Vaysse, Wei Yu, Pierre-Henri Commere, Quentin Holleville, Tristan Espie-Caullet, Richard Frock and Ludovic Deriano ()
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Timea Marton: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
Jinglong Wang: Stanford University, Department of Radiation Oncology, School of Medicine
Amaury Vaysse: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
Wei Yu: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
Pierre-Henri Commere: Université Paris Cité, Flow Cytometry Platform, Institut Pasteur
Quentin Holleville: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
Tristan Espie-Caullet: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
Richard Frock: Stanford University, Department of Radiation Oncology, School of Medicine
Ludovic Deriano: Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Non-homologous end joining (NHEJ) is the primary pathway for repairing G1 phase-induced DNA double-strand breaks (DSBs) during immunoglobulin heavy chain (Igh) class switch recombination (CSR) in B lymphocytes. In B cells lacking NHEJ (XRCC4) or DSB end protection (SHLD1), end joining during CSR proceeds through an alternative end-joining pathway. Polymerase theta (Pol θ) is widely regarded as a mediator of this pathway, essential for repairing replication-associated DSBs during mitosis when homologous recombination is unavailable. In this study, we examined CSR in primary B cells lacking XRCC4, SHLD1, and/or Pol θ, revealing two repair pathways: Pol θ-independent productive switching and Pol θ-dependent unproductive switching characterized by end resection, inversion and microhomology. Furthermore, we show that Pol θ-mediated repair under NHEJ-deficiency coincides with G1-to-S phase transition and occurs independently of RHINO and PLK1. Thus, in the absence of NHEJ, Pol θ repairs persistent G1-phase DSBs during S-phase rather than mitosis.

Date: 2025
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DOI: 10.1038/s41467-025-65555-9

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