DNA-PK-mediated CRTC2 phosphorylation promotes NHEJ and suppresses antitumor immunity via relocation to repair complexes
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de 20 patients atteints d'un cancer du foie, cette étude met en évidence un mécanisme par lequel la phosphorylation du coactivateur transcriptionnel CRTC2, induite par la protéine kinase dépendante de l'ADN, favorise la jonction d'extrémités non homologues et supprime l'immunité antitumorale via la dissociation du coactivateur des complexes transcriptionnels et son incorporation dans des complexes de réparation au niveau des cassures de l'ADN
Genotoxic stress or exogenous DNA damage induces transcription arrest, enabling efficient DNA repair. Transcription activators directly participate in DNA damage repair (DDR), but the trans-regulatory mechanisms linking transcription and DDR remain elusive. Here we reveal that CRTC2 switches from a transcriptional coactivator to a DNA-damage responder. CRTC2 promotes non-homologous end joining (NHEJ) in vitro and in vivo. Mechanistically, PARP1 recruits CRTC2 to DNA breaks, where CRTC2 promotes DNA-PKcs enrichment and DNA-PK holoenzyme assembly, driving NHEJ. DNA-PK phosphorylates CRTC2 at Ser433, dissociating it from transcriptional complexes to suppress target gene transcription and promoting its incorporation into repair complexes, forming a positive feedback loop that enhances NHEJ. CRTC2 loss radiosensitizes liver cancer cells, potentiates irradiation-induced cGAS–STING activation, and promotes antitumor immunity and the abscopal effect. AAV8-mediated targeting of CRTC2 sensitizes tumors to radioimmunotherapy. Thus, CRTC2 couples transcriptional silencing to DNA repair, and its inhibition offers a promising strategy for radioimmunotherapy sensitization.
Nature Communications , article en libre accès, 2026