SAMHD1-mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination

EMBO J. 2020 Aug 3;39(15):e102931. doi: 10.15252/embj.2019102931. Epub 2020 Jun 8.

Abstract

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, regulates the levels of cellular dNTPs through their hydrolysis. SAMHD1 protects cells from invading viruses that depend on dNTPs to replicate and is frequently mutated in cancers and Aicardi-Goutières syndrome, a hereditary autoimmune encephalopathy. We discovered that SAMHD1 localizes at the immunoglobulin (Ig) switch region, and serves as a novel DNA repair regulator of Ig class switch recombination (CSR). Depletion of SAMHD1 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 SAMHD1 deficiency during activation-induced cytidine deaminase-mediated genomic instability. Interestingly, CSR induced by staggered but not blunt, double-stranded DNA breaks was impaired by SAMHD1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose that SAMHD1-mediated dNTP balance regulates dNTP-sensitive DNA end-processing enzyme and promotes CSR and aberrant genomic rearrangements by suppressing the insertional DNA repair pathway.

Keywords: AICDA; dNTP; DNA repair; SAMHD1; genomic instability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Repair*
  • Deoxyribonucleotides / genetics
  • Deoxyribonucleotides / metabolism*
  • Humans
  • Immunoglobulin Class Switching*
  • SAM Domain and HD Domain-Containing Protein 1 / genetics
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism*

Substances

  • Deoxyribonucleotides
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human