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

Author

Listed:
  • 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
    Bioinformatics and Biostatistics Hub, Institut Pasteur, Université Paris Cité)

  • Wei Yu

    (Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity
    Xi’an, BioBank, The First Affiliated Hospital of Xi’an Jiaotong University)

  • 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)

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.

Suggested Citation

  • Timea Marton & Jinglong Wang & Amaury Vaysse & Wei Yu & Pierre-Henri Commere & Quentin Holleville & Tristan Espie-Caullet & Richard Frock & Ludovic Deriano, 2025. "Polymerase theta repairs persistent G1-induced DNA breaks in S-phase during class switch recombination," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65555-9
    DOI: 10.1038/s41467-025-65555-9
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