RNA polymerase II degradation triggered by DNA repair occurs in trans and independently of how the lesion is recognized.

In response to DNA damage, RPB1, the catalytic subunit of RNA Polymerase II (RNAPII), is degraded by the ubiquitin-proteasome system. Degradation models only consider transcriptionally engaged molecules, where a stalled RNAPII complex functions as a lesion-recognition factor, and its RPB1 subunit is proposed to be subsequently degraded to facilitate access of lesion-processing nucleotide excision repair (NER) factors. This transcription-coupled repair is complemented by the global genome repair (GG-NER) system, where lesions are recognized by the XPC and DDB2 factors. Here, we show that RPB1 degradation is controlled in trans by a pathway that depends on lesion processing by NER, irrespectively of whether the lesion is recognized by RNAPII itself or by XPC-DDB2. Incomplete repair due to absence of lesion-processing factors (XPA, XPB, XPD, XPF, or XPG) enhances RPB1 degradation, indicating that the signal controlling RPB1 abundance is started by lesion recognition and continues until DNA repair is completed. Consistent with an in trans mechanism, damage-induced RPB1 degradation is not restricted to active nor phosphorylated RPB1 molecules and depends on Cullin-RING ubiquitin ligases. These findings uncover a repair-dependent mechanism controlling RPB1 levels and provide a rationale for the control of gene expression under stress, where more damage implies more repair and less RPB1 levels, hence restricting RNAPII activity.