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SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

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(...

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Detalles Bibliográficos
Autores principales: Vincendeau, Estelle, Wei, Wenming, Zhang, Xuefei, Planchais, Cyril, Yu, Wei, Lenden-Hasse, Hélène, Cokelaer, Thomas, Pipoli da Fonseca, Juliana, Mouquet, Hugo, Adams, David J., Alt, Frederick W., Jackson, Stephen P., Balmus, Gabriel, Lescale, Chloé, Deriano, Ludovic
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240092/
https://www.ncbi.nlm.nih.gov/pubmed/35764636
http://dx.doi.org/10.1038/s41467-022-31287-3
Descripción
Sumario: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.