Decrotonylation of cGAS K254 prompts homologous recombination repair by blocking its DNA binding and releasing PARP1.
J Biol Chem
; 300(8): 107554, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-39002667
ABSTRACT
Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, also exhibits nuclear genomic localization and is involved in DNA damage signaling. In this study, we investigated the impact of cGAS crotonylation on the regulation of the DNA damage response, particularly homologous recombination repair, following exposure to ionizing radiation (IR). Lysine 254 of cGAS is constitutively crotonylated by the CREB-binding protein; however, IR-induced DNA damage triggers sirtuin 3 (SIRT3)-mediated decrotonylation. Lysine 254 decrotonylation decreased the DNA-binding affinity of cGAS and inhibited its interaction with PARP1, promoting homologous recombination repair. Moreover, SIRT3 suppression led to homologous recombination repair inhibition and markedly sensitized cancer cells to IR and DNA-damaging chemicals, highlighting SIRT3 as a potential target for cancer therapy. Overall, this study revealed the crucial role of cGAS crotonylation in the DNA damage response. Furthermore, we propose that modulating cGAS and SIRT3 activities could be potential strategies for cancer therapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Sirtuina 3
/
Reparación del ADN por Recombinación
/
Poli(ADP-Ribosa) Polimerasa-1
/
Nucleotidiltransferasas
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
/
J. biol. chem
/
Journal of biological chemistry
Año:
2024
Tipo del documento:
Article
País de afiliación:
China