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

  • Nat Commun. 2025 Nov 26;16(1):10536. doi: 10.1038/s41467-025-65555-9.
Timea Marton  1 ,  Jinglong Wang  2 ,  Amaury Vaysse  1  3 ,  Wei Yu  1  4 ,  Pierre-Henri Commere  5 ,  Quentin Holleville  1 ,  Tristan Espie-Caullet  1 ,  Richard Frock  2 ,  Ludovic Deriano  6
Affiliations
  • 1. Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit, Paris, France.
  • 2. Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, CA, USA.
  • 3. Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France.
  • 4. BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Xi'an, P.R. China.
  • 5. Flow Cytometry Platform, Institut Pasteur, Université Paris Cité, Paris, France.
  • 6. Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit, Paris, France. [email protected].
PMID: 41298353 DOI: 10.1038/s41467-025-65555-9
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.

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