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<p>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.</p>

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DNA-PK-mediated CRTC2 phosphorylation promotes NHEJ and suppresses antitumor immunity via relocation to repair complexes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Fangdi Zou,
  • Zhiqi Yao,
  • Xiaohan Dong,
  • Yang Liu,
  • Zhanjie Xiu,
  • Meixi Wang,
  • Xiaofeng Liu,
  • Xinlu Wang,
  • Lin Sun,
  • Jian Wang,
  • Shuai Ma,
  • Heng Zhang,
  • Kaishun Hu,
  • Yan Sun,
  • Kexin Chen,
  • Zhiyong Yuan,
  • Lei Shi,
  • Zhiqiang Wu,
  • Zeyun Mi

摘要

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.