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

Yongchang Zhu, Xiping Zhang, Meng Gao, Yanchao Huang, Yuanqing Tan, Avital Parnas, Sizhong Wu, Delin Zhan, Sheera Adar and Jinchuan Hu ()
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Yongchang Zhu: Fudan University
Xiping Zhang: Fudan University
Meng Gao: Fudan University
Yanchao Huang: Fudan University
Yuanqing Tan: Fudan University
Avital Parnas: The Hebrew University of Jerusalem
Sizhong Wu: Fudan University
Delin Zhan: Fudan University
Sheera Adar: The Hebrew University of Jerusalem
Jinchuan Hu: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51463-x

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