The 3 '-flap endonuclease XPF-ERCC1 promotes alternative end joining and chromosomal translocation during B cell class switching

Robust alternative end joining (A-EJ) in classical non-homologous end joining (c-NHEJ)-deficient murine cells features double-strand break (DSB) end resection and microhomology (MH) usage and promotes chromosomal translocation. The activities responsible for removing 3' single-strand overhangs following resection and MH annealing in A-EJ remain unclear. We show that, during class switch recombination (CSR) in mature mouse B cells, the structure-specific endonuclease complex XPF-ERCC1SLX4, although not required for normal CSR, represents a nucleotide-excision-repair-independent 3' flap removal activity for A-EJ-mediated CSR. B cells deficient in DNA ligase 4 and XPF-ERCC1 exhibit further impaired class switching, reducing joining to the resected S region DSBs without altering the MH pattern in S-S junctions. In ERCC1-deficient A-EJ cells, 3' single-stranded DNA (ssDNA) flaps that are generated predominantly in S/G2 phase of the cell cycle are susceptible to nuclease resolution. Moreover, ERCC1 promotes c-myc-IgH translocation in Lig4(-/-) cells. Our study reveals an important role of the flap endonuclease XPF-ERCC1 in A-EJ and oncogenic translocation in mouse B cells.

Automated summary

The study reveals a critical role of the flap endonuclease XPF-ERCC1 in A-EJ and oncogenic translocation in mouse B cells during class switch recombination (CSR). XPF-ERCC1SLX4 complex helps in achieving CSR in B cells, while deficiency of DNA ligase 4 and XPF-ERCC1 leads to impaired class switching process. ERCC1 plays an important role in resolving 3' single-stranded DNA flaps.