SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus. (17th June 2020)

• Record Type: Journal Article
• Authors: Ling, Alexanda K; Munro, Meagan; Chaudhary, Natasha; Li, Conglei; Berru, Maribel; Wu, Brendan; Durocher, Daniel; Martin, Alberto
• Is Part Of: EMBO reports. Volume 21:Number 8(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-06-17
• Subjects: B cell -- BRCA1 -- class switch recombination -- shieldin -- Shld2−/− mouse; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949823
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 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 SHLD2 can suppress the embryonic lethality of a Brca1 Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2 −/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 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 SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis: The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues Brca Δ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2 −/− primary B‐cells have impaired ex vivo and in vivo CSR. A significant and heretofore undescribed Ig lo population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells. Ig lo cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Abstract : The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues Brca Δ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection.