SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination.
Pipoli da Fonseca, Juliana
Alt, Frederick W
Springer Science and Business Media LLC
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Vincendeau, E., Wei, W., Zhang, X., Planchais, C., Yu, W., Lenden-Hasse, H., Cokelaer, T., et al. (2022). SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-31287-3
Funder: Ligue Nationale Contre le Cancer
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.
Article, /631/250/2152/2498, /631/337/1427/2122, /631/337/149, /631/250/2152/2497, /13/1, /13/21, /13/31, /13/106, /45, /45/23, /45/71, /45/77, /49, article
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
European Commission Horizon 2020 (H2020) ERC (855741)
External DOI: https://doi.org/10.1038/s41467-022-31287-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338596