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 () and Ludovic Deriano ()
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Estelle Vincendeau: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit
Wenming Wei: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit
Xuefei Zhang: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, Department of Genetics, Harvard Medical School
Cyril Planchais: Institut Pasteur, Université de Paris, INSERM U1222, Laboratory of Humoral Immunology
Wei Yu: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit
Hélène Lenden-Hasse: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit
Thomas Cokelaer: Institut Pasteur, Plate-forme Technologique Biomics, Centre de Ressources et Recherches Technologiques
Juliana Pipoli da Fonseca: Institut Pasteur, Plate-forme Technologique Biomics, Centre de Ressources et Recherches Technologiques
Hugo Mouquet: Institut Pasteur, Université de Paris, INSERM U1222, Laboratory of Humoral Immunology
David J. Adams: Wellcome Trust Sanger Institute
Frederick W. Alt: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, Department of Genetics, Harvard Medical School
Stephen P. Jackson: Wellcome Trust/Cancer Research UK Gurdon Institute, Department of Biochemistry, University of Cambridge
Gabriel Balmus: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, University of Cambridge
Chloé Lescale: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit
Ludovic Deriano: Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Immunity and Cancer Unit

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31287-3

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