Journal Article

Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans

Adelman, Karen, Lis, John T.

2012

Overview

Key Points Pausing is now recognized to be a pervasive feature of promoters in mammals and Drosophila melanogaster , and the evidence supporting this from genome-wide studies is presented. The nomenclature of different promoter-associated RNA polymerase II (Pol II) species is explicitly defined in an effort to provide consistency in future literature. The known mechanistic features of Pol II pausing and its release to productive elongation are described. Most genes are associated with factors that establish and release paused Pol II and therefore appear to progress through this step, although only a subset of genes appears to be directly regulated by pausing. Multiple lines of evidence support the idea that Pol II and nucleosomes compete for promoter binding and suggest that a crucial role of paused Pol II involves maintenance of accessible promoter chromatin architecture. Although pausing has been connected to extremely rapid and synchronous activation of genes, pausing is also highly associated with constitutively expressed genes that encode signalling and transcription factors. Pausing provides a mechanism to tune these key genes to cellular and external regulatory cues. Pausing provides a point of regulation that is distinct from Pol II recruitment and initiation, and this may facilitate the integration of multiple cellular signals. Distinct signals that act through diverse targeted transcription factors can regulate different steps in the transcription pathway and provide a highly modulated transcriptional response at individual genes. Pol II pausing and release occur at a point when 5′ end RNA processing and phosphorylation of the Pol II carboxy-terminal domain occurs. We speculate that by coupling RNA processing to the status and activity of Pol II itself, the cell ensures that nascent RNA is properly protected from degradation and efficiently matures into a functional mRNA. Emerging evidence points towards RNA polymerase II promoter-proximal pausing as a widespread regulatory mechanism in higher eukaryotes. Here, the authors discuss the evidence for this from genome-wide studies and present potential functions of this regulatory mechanism. Recent years have witnessed a sea change in our understanding of transcription regulation: whereas traditional models focused solely on the events that brought RNA polymerase II (Pol II) to a gene promoter to initiate RNA synthesis, emerging evidence points to the pausing of Pol II during early elongation as a widespread regulatory mechanism in higher eukaryotes. Current data indicate that pausing is particularly enriched at genes in signal-responsive pathways. Here the evidence for pausing of Pol II from recent high-throughput studies will be discussed, as well as the potential interconnected functions of promoter-proximally paused Pol II.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/200 / 631/337/572 / 631/45/173 / Agriculture / Animal Genetics and Genomics / Animals / Binding Sites / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation - genetics / Gene Function / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Human Genetics / Humans / Metazoa / Models, Biological / Promoter Regions, Genetic - genetics / Promoters (Genetics) / Protein Binding - physiology / Regulatory Sequences, Nucleic Acid - genetics / Regulatory Sequences, Nucleic Acid - physiology / review-article / RNA polymerase / RNA Polymerase II - metabolism / RNA Polymerase II - physiology / RNA polymerases / Transcription factors / Transcription, Genetic - physiology