SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination.
- Abstract:
- SHLD1 is part of the Shieldin (SHLD) complex, which acts downstream of 53BP1 to counteract DNA double-strand break (DSB) end resection and promote DNA repair via non-homologous end-joining (NHEJ). While 53BP1 is essential for immunoglobulin heavy chain class switch recombination (CSR), long-range V(D)J recombination and repair of RAG-induced DSBs in XLF-deficient cells, the function of SHLD during these processes remains elusive. Here we report that SHLD1 is dispensable for lymphocyte development and RAG-mediated V(D)J recombination, even in the absence of XLF. By contrast, SHLD1 is essential for restricting resection at AID-induced DSB ends in both NHEJ-proficient and NHEJ-deficient B cells, providing an end-protection mechanism that permits productive CSR by NHEJ and alternative end-joining. Finally, we show that this SHLD1 function is required for orientation-specific joining of AID-initiated DSBs. Our data thus suggest that 53BP1 promotes V(D)J recombination and CSR through two distinct mechanisms: SHLD-independent synapsis of V(D)J segments and switch regions within chromatin, and SHLD-dependent protection of AID-DSB ends against resection.
- Authors:
- E Vincendeau, W Wei, X Zhang, C Planchais, W Yu, H Lenden-Hasse, T Cokelaer, J Pipoli da Fonseca, H Mouquet, DJ Adams, FW Alt, SP Jackson, G Balmus, C Lescale, L Deriano
- Journal:
- Nat Commun
- Citation info:
- 13(1):3707
- Publication date:
- 28th Jun 2022
- Full text
- DOI