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<p>Cells use transcription-coupled nucleotide excision repair (TC-NER) to efficiently resolve transcription-blocking DNA lesions caused by genotoxic stress such as ultraviolet (UV) irradiation. However, UV also induces RNA damage, triggering a cytoplasmic ribotoxic stress response (RSR). Whether and how RSR affects nuclear TC-NER has remained unclear. Here we identify INTS12, a flexible, poorly characterized subunit of the Integrator complex, as a key mediator linking RSR to TC-NER. Specifically, RSR-activated ZAK signaling induces phosphorylation of INTS12, enhancing its interaction with CSB and promoting recruitment of the Integrator complex to lesion-stalled RNA polymerase II (Pol II). This facilitates Pol II clearance and enables efficient DNA repair through TC-NER. Disruption of this pathway compromises TC-NER and transcription recovery, thereby increasing cellular sensitivity to UV-induced damage. Notably, the requirement for INTS12-mediated Pol II removal is context dependent, as it is not advantageous during the transcription-coupled response to formaldehyde-induced DNA–protein crosslinks, which rely on a distinct proteasome-dependent degradation pathway. Together, these findings uncover a regulatory axis connecting RNA damage signaling to DNA repair and highlight a context-dependent role of INTS12 in maintaining genome integrity.</p>

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Integrator subunit INTS12 links ribotoxic stress to transcription-coupled nucleotide excision repair

  • 期刊论文

  • 发表日期：

    2026年2月26日

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  • Zhuo Li,
  • Ran Li,
  • Min Yang,
  • Yanchao Huang,
  • Jiaye Yang,
  • Qian Zhu,
  • Yangqing Shao,
  • Weiqi Zhao,
  • Huanyi Fu,
  • Yu-Xin Xiao,
  • Chengyu Li,
  • Huipeng Jiao,
  • Dong Fang,
  • Bing Yang,
  • Yi Lu,
  • Jun Xu,
  • Lei Li,
  • Jun Huang,
  • Fei Xavier Chen,
  • Long Zhang,
  • Jinchuan Hu,
  • Huasong Lu

摘要

Cells use transcription-coupled nucleotide excision repair (TC-NER) to efficiently resolve transcription-blocking DNA lesions caused by genotoxic stress such as ultraviolet (UV) irradiation. However, UV also induces RNA damage, triggering a cytoplasmic ribotoxic stress response (RSR). Whether and how RSR affects nuclear TC-NER has remained unclear. Here we identify INTS12, a flexible, poorly characterized subunit of the Integrator complex, as a key mediator linking RSR to TC-NER. Specifically, RSR-activated ZAK signaling induces phosphorylation of INTS12, enhancing its interaction with CSB and promoting recruitment of the Integrator complex to lesion-stalled RNA polymerase II (Pol II). This facilitates Pol II clearance and enables efficient DNA repair through TC-NER. Disruption of this pathway compromises TC-NER and transcription recovery, thereby increasing cellular sensitivity to UV-induced damage. Notably, the requirement for INTS12-mediated Pol II removal is context dependent, as it is not advantageous during the transcription-coupled response to formaldehyde-induced DNA–protein crosslinks, which rely on a distinct proteasome-dependent degradation pathway. Together, these findings uncover a regulatory axis connecting RNA damage signaling to DNA repair and highlight a context-dependent role of INTS12 in maintaining genome integrity.