A role for the Cockayne Syndrome B (CSB)-Elongin ubiquitin ligase complex in signal-dependent RNA polymerase II transcription

The Elongin complex was originally identified as an RNA polymerase II (RNAPII) elongation factor and subsequently as the substrate recognition component of a Cullin-RING E3 ubiquitin ligase. More recent evidence indicates that the Elongin ubiquitin ligase assembles with the Cockayne syndrome B helicase (CSB) in response to DNA damage and can target stalled polymerases for ubiquitylation and removal from the genome. In this report, we present evidence that the CSB-Elongin ubiquitin ligase pathway has roles beyond the DNA damage response in the activation of RNAPII-mediated transcription. We observed that assembly of the CSB-Elongin ubiquitin ligase is induced not just by DNA damage, but also by a variety of signals that activate RNAPII-mediated transcription, including endoplasmic reticulum (ER) stress, amino acid starvation, retinoic acid, glucocorticoids, and doxycycline treatment of cells carrying several copies of a doxycycline-inducible reporter. Using glucocorticoid receptor (GR)-regulated genes as a model, we showed that glucocorticoid-induced transcription is accompanied by rapid recruitment of CSB and the Elongin ubiquitin ligase to target genes in a step that depends upon the presence of transcribing RNAPII on those genes. Consistent with the idea that the CSB-Elongin pathway plays a direct role in GR-regulated transcription, mouse cells lacking the Elongin subunit Elongin A exhibit delays in both RNAPII accumulation on and dismissal from target genes following glucocorticoid addition and withdrawal, respectively. Taken together, our findings bring to light a new role for the CSB-Elongin pathway in RNAPII-mediated transcription.

Automated summary

The CSB-Elongin ubiquitin ligase pathway not only plays a role in the response to DNA damage, but also has a significant impact on the activation of RNAPII-mediated transcription in various signaling pathways, such as endoplasmic reticulum stress, amino acid starvation, retinoic acid, glucocorticoids, and doxycycline. The pathway is involved in the rapid recruitment of CSB and the Elongin ubiquitin ligase to target genes during transcription, suggesting a direct role in gene regulation. Cells lacking the Elongin subunit Elongin A exhibit delays in RNAPII accumulation and dismissal from target genes following hormone treatments, indicating the importance of this pathway in transcription regulation.