At the heart of the central dogma, eukaryotic RNA polymerase II (Pol II) transcribes all protein coding genes and thousands of non-coding RNAs. The gene expression output is largely regulated in a small region close to the transcription start site (TSS), where an array of factors controlling transcription initiation and promoter-proximal pausing determine how many Pol II molecules are released into the gene, per unit of time. I will present recent work from our lab that reveals a new transcriptional checkpoint: ubiquitin-mediated quality control (QC) of Pol II in the promoter-proximal zone.

After Pol II passes promoter-proximal checkpoints and is released into the gene, it still has to complete a long journey: some human genes are hundreds of kilobases long and can take hours or even days to transcribe a single (m)RNA copy. While elongating through genes, Pol II faces many obstacles, such as DNA-bound proteins, secondary DNA structures and DNA damage, which impede its progression and cause it to stall. We recently discovered a new pathway that protects Pol II from stalling, and I will present this work in the second part of my talk.