Regulation of RNA transcript elongation in metazoans and its relevance to disease

Our understanding of transcript elongation by metazoan RNA polymerase II (Pol II) has grown notably in recent years. Advances in structural biology have defined the interactions that underlie promoter-proximal pausing of Pol II and the transition from pausing to productive elongation. Improved targeted protein degradation together with sensitive, time-resolved assays of RNA synthesis has transformed our view of transcript elongation control in living cells. In this Review, we discuss the highly orchestrated interactions between elongating Pol II and co-transcriptional RNA-processing factors, revealing that the splicing factor U1 small nuclear ribonucleoprotein (U1 snRNP) directly stimulates productive elongation. Biochemical and cell-based techniques have shed new light on how Pol II overcomes obstacles to elongation such as nucleosomes. Emerging studies have demonstrated the importance of quality control during early transcript elongation by factors such as Integrator and Restrictor. These surveillance machineries ensure the integrity of mRNA synthesis and suppress spurious RNAs arising from transposable elements or regulatory regions such as enhancers. Finally, we discuss how defects in Pol II elongation contribute to diseases ranging from developmental disorders to cancer and inflammation, emphasizing the importance of a fuller understanding of Pol II elongation to human health.