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SAMHD1-mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination.
The EMBO Journal ( IF 11.4 ) Pub Date : 2020-06-08 , DOI: 10.15252/embj.2019102931
Afzal Husain 1 , Jianliang Xu 1 , Hodaka Fujii 2, 3 , Mikiyo Nakata 1 , Maki Kobayashi 1 , Ji-Yang Wang 4 , Jan Rehwinkel 5 , Tasuku Honjo 1 , Nasim A Begum 1
Affiliation  

Sterile alpha motif and histidine‐aspartic acid domain‐containing protein 1 (SAMHD 1), a dNTP triphosphohydrolase, regulates the levels of cellular dNTP s through their hydrolysis. SAMHD 1 protects cells from invading viruses that depend on dNTP s to replicate and is frequently mutated in cancers and Aicardi–Goutières syndrome, a hereditary autoimmune encephalopathy. We discovered that SAMHD 1 localizes at the immunoglobulin (Ig) switch region, and serves as a novel DNA repair regulator of Ig class switch recombination (CSR ). Depletion of SAMHD 1 impaired not only CSR but also IgH /c‐Myc translocation. Consistently, we could inhibit these two processes by elevating the cellular nucleotide pool. A high frequency of nucleotide insertion at the break‐point junctions is a notable feature in SAMHD 1 deficiency during activation‐induced cytidine deaminase‐mediated genomic instability. Interestingly, CSR induced by staggered but not blunt, double‐stranded DNA breaks was impaired by SAMHD 1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose that SAMHD 1‐mediated dNTP balance regulates dNTP ‐sensitive DNA end‐processing enzyme and promotes CSR and aberrant genomic rearrangements by suppressing the insertional DNA repair pathway.

中文翻译:

SAMHD1 介导的 dNTP 降解是抗体类别转换重组期间有效 DNA 修复所必需的。

无菌 α 基序和含组氨酸天冬氨酸结构域蛋白 1 (SAMHD 1),一种 dNTP 三磷酸水解酶,通过水解调节细胞 dNTP 的水平。SAMHD 1 保护细胞免受入侵病毒的侵害,这些病毒依赖 dNTP 进行复制,并且在癌症和 Aicardi-Goutières 综合征(一种遗传性自身免疫性脑病)中经常发生突变。我们发现 SAMHD 1 定位于免疫球蛋白 (Ig) 开关区域,并充当 Ig 类开关重组 (CSR) 的新型 DNA 修复调节剂。SAMHD 1 的消耗不仅会损害 CSR,还会损害IgH / c-Myc易位。一致地,我们可以通过提高细胞核苷酸库来抑制这两个过程。在激活诱导的胞苷脱氨酶介导的基因组不稳定性期间,断点连接处核苷酸插入的高频率是 SAMHD 1 缺陷的一个显着特征。有趣的是,由交错但非钝性双链 DNA 断裂诱导的 CSR 受到 SAMHD 1 消耗的影响,伴随着重组连接处核苷酸插入的增加。我们提出 SAMHD 1 介导的 dNTP 平衡调节 dNTP 敏感的 DNA 末端加工酶,并通过抑制插入 DNA 修复途径促进 CSR 和异常基因组重排。
更新日期:2020-08-03
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