SAMHD1-mediateddNTPdegradation is required for efficientDNArepair during antibody class switch recombination

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1), adNTPtriphosphohydrolase, regulates the levels of cellulardNTPs through their hydrolysis.SAMHD1 protects cells from invading viruses that depend ondNTPs to replicate and is frequently mutated in cancers and Aicardi-Goutieres syndrome, a hereditary autoimmune encephalopathy. We discovered thatSAMHD1 localizes at the immunoglobulin (Ig) switch region, and serves as a novelDNArepair regulator of Ig class switch recombination (CSR). Depletion ofSAMHD1 impaired not onlyCSRbut alsoIgH/c-Myctranslocation. 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 inSAMHD1 deficiency during activation-induced cytidine deaminase-mediated genomic instability. Interestingly,CSRinduced by staggered but not blunt, double-strandedDNAbreaks was impaired bySAMHD1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose thatSAMHD1-mediateddNTPbalance regulatesdNTP-sensitiveDNAend-processing enzyme and promotesCSRand aberrant genomic rearrangements by suppressing the insertionalDNArepair pathway.