Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II

  • Nat Commun. 2024 Aug 17;15(1):7089. doi: 10.1038/s41467-024-51463-x.
Yongchang Zhu  #  1 ,  Xiping Zhang  #  1 ,  Meng Gao  #  1 ,  Yanchao Huang  1 ,  Yuanqing Tan  1 ,  Avital Parnas  2 ,  Sizhong Wu  1 ,  Delin Zhan  1 ,  Sheera Adar  2 ,  Jinchuan Hu  3
Affiliations
  • 1. Shanghai Fifth People's Hospital of Fudan University, 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.
  • 2. Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.
  • 3. Shanghai Fifth People's Hospital of Fudan University, 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].
  • # Contributed equally.
PMID: 39154022 DOI: 10.1038/s41467-024-51463-x
Abstract

Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repair's prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7's Deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

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