DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect [RNA-Seq]

DNA damage repair and transcription are antagonistic cellular processes that require precise spatiotemporal coordination to maintain genomic integrity. Transcriptional silencing at DSB sites is essential for efficient repair, mediated through localized histone modifications and direct inhibition of RNA polymerase II (Pol II). However, the role of transcriptional activators in coordinating DSB repair with transcriptional silencing remains elusive. Here, we identify the transcriptional coactivator CRTC2 as a key coordinator of DNA repair and transcriptional regulation. We demonstrate that CRTC2 promotes canonical non-homologous end joining (c-NHEJ) both in vitro and in vivo. Mechanistically, PARP1 activation recruits CRTC2 to DNA breaks, where it facilitates DNA-PKcs recruitment and assembly of the DNA-PK holoenzyme, thereby driving c-NHEJ. DNA-PK–mediated phosphorylation of CRTC2 at Ser433 dissociates it from transcriptional complexes, suppressing target gene transcription, and promoting its incorporation into DNA repair complexes. Thus, establishing a positive feedback loop that enhances NHEJ efficiency. CRTC2 loss radiosensitizes cancer cells, potentiates irradiation-induced cGAS–STING activation, promotes cytotoxic CD8⁺ T cell infiltration, and enhances the abscopal effect. Furthermore, AAV8-mediated targeting of CRTC2 sensitizes tumors to radioimmunotherapy. Our results reveal CRTC2 as bifunctional nodal effector coupling transcriptional silencing to DNA repair and propose its inhibition as a promising strategy for radioimmunotherapy sensitization in resistant malignancies.