SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity.
Sci Adv
; 9(24): eade6624, 2023 06 16.
Article
en En
| MEDLINE
| ID: mdl-37315132
ABSTRACT
DNA damage repair (DDR) is a double-edged sword with different roles in cancer susceptibility and drug resistance. Recent studies suggest that DDR inhibitors affect immune surveillance. However, this phenomenon is poorly understood. We report that methyltransferase SMYD2 plays an essential role in nonhomologous end joining repair (NHEJ), driving tumor cells adaptive to radiotherapy. Mechanically, in response to DNA damage, SMYD2 is mobilized onto chromatin and methylates Ku70 at lysine-74, lysine-516, and lysine-539, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Knockdown of SMYD2 or its inhibitor AZ505 results in persistent DNA damage and improper repair, which sequentially leads to accumulation of cytosolic DNA, and activation of cGAS-STING pathway and triggers antitumor immunity via infiltration and activation of cytotoxic CD8+ T cells. Our study reveals an unidentified role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting that SMYD2 is a promising therapeutic target for cancer treatment.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
N-Metiltransferasa de Histona-Lisina
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Linfocitos T CD8-positivos
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Reparación del ADN por Unión de Extremidades
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Autoantígeno Ku
Idioma:
En
Revista:
Sci Adv
Año:
2023
Tipo del documento:
Article
País de afiliación:
China