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SAMHD 1‐mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination
Author(s) -
Husain Afzal,
Xu Jianliang,
Fujii Hodaka,
Nakata Mikiyo,
Kobayashi Maki,
Wang JiYang,
Rehwinkel Jan,
Honjo Tasuku,
Begum Nasim A
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102931
Subject(s) - biology , recombination , immunoglobulin class switching , degradation (telecommunications) , genetics , microbiology and biotechnology , antibody , gene , b cell , computer science , telecommunications
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.