Link to Pubmed [PMID] – 41298353
Link to DOI – 10.1038/s41467-025-65555-9
Nat Commun. 2025 Nov 26; 16(1):10536
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 char-
acterized 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.