PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II

The control of promoter-proximal pausing and the release of RNA polymerase II (Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify that Pol-II-associated factor 1 (PAF1) possesses an evolutionarily conserved function in metazoans in the regulation of promoter-proximal pausing. Reduction in PAF1 levels leads to an increased release of paused Pol II into gene bodies at thousands of genes. PAF1 depletion results in increased nascent and mature transcripts and increased levels of phosphorylation of Pol II’s C-terminal domain on serine 2 (Ser2P). These changes can be explained by the recruitment of the Ser2P kinase super elongation complex (SEC) effecting increased release of paused Pol II into productive elongation, thus establishing PAF1 as a regulator of promoter-proximal pausing by Pol II. [Display omitted] •PAF1 loss results in release of Pol II into gene bodies at thousands of genes•Genes exhibiting high degrees of pausing are more affected by loss of PAF1•Redistribution of Pol II is associated with increased transcription•PAF1 depletion leads to increased recruitment of the super elongation complex PAF1 plays the role of gatekeeper for Pol II promoter-proximal pausing, with its loss enhancing the transcription of thousands of genes.