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Nat Commun ; 12(1): 6207, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34707113

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation), in which cGAMP reduces cellular levels of NAD+; meanwhile, restoring NAD+ levels abrogates cGAMP-mediated suppression of PARylation and HDR. Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN (Crassostrea virginica and Nematostella vectensis), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity.


Assuntos
Dano ao DNA , Nucleotídeos Cíclicos/metabolismo , Transdução de Sinais , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Crassostrea/genética , Crassostrea/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Nucleotidiltransferases/metabolismo , Fosforilação , Poli ADP Ribosilação , Proteínas Serina-Treonina Quinases/metabolismo , Reparo de DNA por Recombinação , Anêmonas-do-Mar/genética , Anêmonas-do-Mar/metabolismo
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