SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation.

ABSTRACT: Activation-induced deaminase (AID) initiates hypermutation of Ig genes in activated B cells by converting C:G into U:G base pairs. G₁-phase variants of uracil base excision repair (BER) and mismatch repair (MMR) then deploy translesion polymerases including REV1 and Pol η, which exacerbates mutation. dNTP paucity may contribute to hypermutation, because dNTP levels are reduced in G₁ phase to inhibit viral replication. To derestrict G₁-phase dNTP supply, we CRISPR-inactivated SAMHD1 (which degrades dNTPs) in germinal center B cells. Samhd1 inactivation increased B cell virus susceptibility, increased transition mutations at C:G base pairs, and substantially decreased transversion mutations at A:T and C:G base pairs in both strands. We conclude

SUBMITTER: Thientosapol ES 

PROVIDER: S-EPMC5948975 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature