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Yongchang Zhu

As the first author of this study, I am grateful for the opportunity to share our perspective on the significance of our findings. In this work, we sought to address a fundamental question in the field of genome maintenance: how cells coordinate the resolution of transcription-blocking lesions (TBLs) when transcription-coupled repair (TCR) is compromised.

By leveraging our recently developed PADD-seq technique, we were able to directly measure the physical interaction between RNA polymerase II (Pol II) and DNA lesions across the genome. This allowed us to differentiate between Pol II stalling caused by direct blockage versus global transcriptional stress—a distinction that has been challenging to make using conventional approaches.

Our results reveal a repair-independent mechanism of Pol II eviction that is CSA- and ubiquitination-dependent, but does not require UVSSA or active repair. We found that the p97-proteasome pathway plays a central role in this process, providing an alternative means to clear stalled Pol II when TCR cannot proceed. Interestingly, this pathway is largely inactive in TCR-proficient cells, suggesting a prioritization of repair over eviction under physiological conditions.

Moreover, our data support a model in which the E3 ligase CRL4^CSA is the primary ubiquitin ligase responsible for targeting Pol II in both TCR and repair-independent contexts. Importantly, we show that K1268-linked ubiquitination of the RPB1 subunit, while critical, is not absolutely required for Pol II eviction, implying the existence of redundant or compensatory mechanisms.

This study also offers mechanistic insight into the differential clinical manifestations of TCR-deficient syndromes. Specifically, we propose that the persistence of lesion-stalled Pol II in CSA- or CSB-deficient cells—rather than the mere absence of repair—may underlie the severe neurodegenerative features of Cockayne syndrome. In contrast, UVSSA-deficient cells retain the ability to remove stalled Pol II, which may explain the milder phenotype observed in UV-sensitive syndrome.

We hope this work provides a framework for further exploration into how cells balance transcription, repair, and proteostasis, and how this balance is disrupted in disease. We are especially excited about the potential implications of targeting lesion-stalled Pol II for therapeutic intervention in neurodegeneration and premature aging.