SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation.
Proc Natl Acad Sci U S A
; 115(19): 4921-4926, 2018 05 08.
Article
em En
| MEDLINE
| ID: mdl-29669924
ABSTRACT
Activation-induced deaminase (AID) initiates hypermutation of Ig genes in activated B cells by converting CG into UG 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 CG base pairs, and substantially decreased transversion mutations at AT and CG base pairs in both strands. We conclude that SAMHD1's restriction of dNTP supply enhances AID's mutagenicity and that the evolution of Ig hypermutation included the repurposing of antiviral mechanisms based on dNTP starvation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Ativação Linfocitária
/
Fase G1
/
Hipermutação Somática de Imunoglobulina
/
Proteína 1 com Domínio SAM e Domínio HD
/
Mutação
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Austrália