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Updated: May 20, 2026
Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
Published on: March 5, 2019
DNA-PK-mediated CRTC2 phosphorylation promotes NHEJ and suppresses antitumor immunity via relocation to repair
Fangdi Zou1,2, Zhiqi Yao1,2, Xiaohan Dong1,2
1Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Abstract:
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.
Insights
CRTC2 shifts from transcription to DNA repair, promoting non-homologous end joining (NHEJ). Inhibiting CRTC2 enhances cancer cell radiosensitivity and antitumor immunity, suggesting its potential in radioimmunotherapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Genotoxic stress halts transcription for DNA repair.
- Transcription activators engage in DNA damage repair (DDR), but regulatory links are unclear.
Purpose of the Study:
- To elucidate the role of CRTC2 in linking transcription and DNA damage response.
- To investigate CRTC2's function in DNA repair and its therapeutic potential.
Main Methods:
- Investigated CRTC2's role in non-homologous end joining (NHEJ) in vitro and in vivo.
- Utilized PARP1 recruitment and DNA-PKcs phosphorylation assays.
- Assessed the impact of CRTC2 loss on liver cancer cell radiosensitivity and immune response.
Main Results:
- CRTC2 acts as a DNA-damage responder, promoting NHEJ by facilitating DNA-PK holoenzyme assembly.
- DNA-PK phosphorylation of CRTC2 suppresses transcription and enhances its role in DNA repair, creating a feedback loop.
- CRTC2 deficiency increases radiosensitivity, potentiates cGAS-STING activation, and boosts antitumor immunity.
Conclusions:
- CRTC2 couples transcriptional silencing to DNA repair.
- CRTC2 inhibition is a potential strategy to sensitize tumors to radioimmunotherapy, enhancing antitumor immunity and the abscopal effect.
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