期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-31287-3
关键词
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资金
- Institut Pasteur, Institut National de la Sante et de la Recherche Medicale (Inserm)
- Wordwide Cancer Research [19-0333]
- Ligue Nationale Contre le Cancer (Equipe labellisee 2019)
- Institut National du Cancer (INCa) [PLBIO19-122]
- French Ministry of Higher Education, Research, and Innovation (Doctoral School Bio Sorbonne Paris Cite)
- Fondation pour la Recherche Medicale
- CNBG company, China
- Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK
- Cancer Research UK (CRUK) [DRCPGM\100005, C6946/A24843]
- Wellcome Investigator award [206388/Z/17/Z, 203144]
- ERC Synergy award [855741]
- Institut Pasteur
- INSERM
- Milieu Interieur Program [ANR-10-LABX-69-01]
- Wellcome Trust [206388/Z/17/Z] Funding Source: Wellcome Trust
- European Research Council (ERC) [855741] Funding Source: European Research Council (ERC)
SHLD1 is a component of the Shieldin complex, playing a role in DNA repair via non-homologous end-joining (NHEJ), which is essential for lymphocyte development. However, it is dispensable for lymphocyte development and V(D)J recombination, but essential for class-switching recombination in activated B cells.
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. SHLD1, as a component of the Shieldin (SHLD) complex, mediates DNA repair via non-homologous end-joining (NHEJ), an essential process during lymphocyte development. Here the authors show that SHLD1 is actually dispensable for lymphocyte development and V(D)J recombination, but is essential for class-switching recombination in activated B cells.
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