Integrator subunit INTS12 links ribotoxic stress to transcription-coupled nucleotide excision repair PMID: 41748916

ADC Targets in Oncology

2026-04-10

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

Nat Struct Mol Biol. 2026 May;33(5):838-852. doi: 10.1038/s41594-026-01766-y.

Zhuo Li ^# ¹ , Ran Li ^# ¹ ² , Min Yang ^# ¹ , Yanchao Huang ^# ³ , Jiaye Yang ¹ , Qian Zhu ³ , Yangqing Shao ¹ , Weiqi Zhao ⁴ , Huanyi Fu ¹ , Yu-Xin Xiao ¹ , Chengyu Li ¹ , Huipeng Jiao ¹ , Dong Fang ¹ , Bing Yang ¹ , Yi Lu ⁵ , Jun Xu ⁴ , Lei Li ¹ , Jun Huang ¹ , Fei Xavier Chen ⁶ , Long Zhang ¹ , Jinchuan Hu ⁷ , Huasong Lu ⁸ ⁹

Affiliations

1. Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
2. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, China.
3. Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
4. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
5. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
6. Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Human Phenome Institute, Fudan University, Shanghai, China.
7. Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
8. Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
9. Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
# Contributed equally.

Abstract

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.