SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination
Estelle Vincendeau, Wenming Wei, Xuefei Zhang, Cyril Planchais, Wei Yu, Hélène Lenden-Hasse, Thomas Cokelaer, Juliana Pipoli da Fonseca, Hugo Mouquet, David J. Adams, Frederick W. Alt, Stephen P. Jackson, Gabriel Balmus, Chloé Lescale, Ludovic Deriano
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.