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SHLD 2 promotes class switch recombination by preventing inactivating deletions within the Igh locus
Author(s) -
Ling Alexanda K,
Munro Meagan,
Chaudhary Natasha,
Li Conglei,
Berru Maribel,
Wu Brendan,
Durocher Daniel,
Martin Alberto
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949823
Subject(s) - genetics , recombination , locus (genetics) , biology , immunoglobulin class switching , homologous recombination , gene , antibody , b cell
The newly identified shieldin complex, composed of SHLD 1, SHLD 2, SHLD 3, and REV 7, lies downstream of 53 BP 1 and acts to inhibit DNA resection and promote NHEJ . Here, we show that Shld2 −/− mice have defective class switch recombination ( CSR ) and that loss of SHLD 2 can suppress the embryonic lethality of a Brca1 Δ11 mutation, highlighting its role as a key effector of 53 BP 1. Lymphocyte development and RAG 1/2‐mediated recombination were unaffected by SHLD 2 deficiency. Interestingly, a significant fraction of Shld2 −/− primary B‐cells and 53 BP 1‐ and shieldin‐deficient CH 12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR ; this population of Ig‐negative cells is also seen in other NHEJ ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD 2 is the key effector of 53 BP 1 and critical for CSR in vivo by suppressing large deletions within the Igh locus.