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

• Published in: Nature communications Vol. 15; no. 1; pp. 7089 - 15
• Main Authors: Zhu, Yongchang, Zhang, Xiping, Gao, Meng, Huang, Yanchao, Tan, Yuanqing, Parnas, Avital, Wu, Sizhong, Zhan, Delin, Adar, Sheera, Hu, Jinchuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 17.08.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Damage; DNA damage; DNA sequencing; DNA-directed RNA polymerase; Gene sequencing; Genetic disorders; Lesions; Proteasomes; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; Transcription-coupled repair; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51463-x

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.Transcription-blocking lesions are removed by transcription-coupled repair (TCR). Here the authors show that the p97-proteasome pathway can evict lesion-stalled RNA Pol II independently of repair. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells.