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SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus.
EMBO Reports ( IF 6.5 ) Pub Date : 2020-06-17 , DOI: 10.15252/embr.201949823
Alexanda K Ling 1 , Meagan Munro 2 , Natasha Chaudhary 2 , Conglei Li 1 , Maribel Berru 1 , Brendan Wu 1 , Daniel Durocher 2, 3 , Alberto Martin 1
Affiliation  

The newly identified shieldin complex, composed of SHLD 1, SHLD 2, SHLD 3, and REV 7, lies downstream of 53BP 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 53BP 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 53BP 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 53BP 1 and critical for CSR in vivo by suppressing large deletions within the Igh locus.

中文翻译:

SHLD2 通过防止 Igh 基因座内的失活缺失来促进类转换重组。

新发现的 shieldin 复合物由 SHLD 1、SHLD 2、SHLD 3 和 REV 7 组成,位于 53BP 1 的下游,起到抑制 DNA 切除和促进 NHEJ 的作用。在这里,我们表明,Shld2 - / -小鼠有缺陷类开关重组(CSR)和SHLD 2的损失可以抑制的胚胎致死BRCA1基因Δ11突变,突出了其作为53BP 1.淋巴细胞发育和RAG的关键效应的作用1/2 介导的重组不受 SHLD 2 缺陷的影响。有趣的是,Shld2的很大一部分-/-原代 B 细胞和 53BP 1 和屏蔽缺陷的 CH 12F3-2 B 细胞在 CSR 诱导后永久失去免疫球蛋白的表达;这种 Ig 阴性细胞群也见于其他 NHEJ 缺陷细胞,在 WT 细胞中的程度要小得多。Ig 的这种损失是由于重组加上过度切除和下游受体恒定区中编码外显子的损失。总的来说,这些数据表明 SHLD 2 是 53BP 1 的关键效应物,并且通过抑制Igh基因座内的大缺失对体内CSR 至关重要。
更新日期:2020-08-05
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