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.
Zou et al. (Mon,) studied this question.