2. Academic Validation
  3. Polymerase theta repairs persistent G1-induced DNA breaks in S-phase during class switch recombination

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

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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