1. Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II.
- Author
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Zhu, Yongchang, Zhang, Xiping, Gao, Meng, Huang, Yanchao, Tan, Yuanqing, Parnas, Avital, Wu, Sizhong, Zhan, Delin, Adar, Sheera, and Hu, Jinchuan
- Subjects
RNA Polymerase II ,Humans ,DNA Repair ,Ubiquitination ,Transcription ,Genetic ,DNA Damage ,Ubiquitin-Specific Peptidase 7 ,Valosin Containing Protein ,Proteasome Endopeptidase Complex ,Excision Repair - 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 repairs prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7s 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.
- Published
- 2024