Phosphoregulation of RNAPII transcription from initiation to pausing to termination.

Abstract

Transcription by eukaryotic RNA polymerase II (RNAPII) is regulated both before and after initiation. A prime example of post-initiation control is the promoter-proximal pause, which ensures complete assembly of RNAPII elongation complexes and proper processing of the nascent transcript. Satisfaction of this checkpoint is a step toward production of mature, full-length mRNA, whereas failure to do so can lead to promoter-proximal transcript termination or RNAPII degradation. Both pause establishment and release are regulated by reversible protein phosphorylation. Cyclin-dependent kinase (CDK) 7, associated with initiation factor TFIIH, phosphorylates RNAPII to enable its escape from the promoter and assembly into a paused complex with the DRB sensitivity-inducing factor (DSIF) and Negative Elongation Factor (NELF), while CDK9, the catalytic subunit of positive transcription elongation factor b (P-TEFb), phosphorylates RNAPII, the SPT5 subunit of DSIF, NELF and possibly other proteins to overcome this block to elongation. Multisite phosphorylation of SPT5 by CDK9 times pause release, regulates elongation speed and coordinates transcription with RNA processing. Pause release and processive elongation are favored by phosphorylation of the RNA-binding loop of SPT5, and opposed by protein phosphatase 4 (PP4) and Integrator-associated protein phosphatase 2A (PP2A), while the stimulatory effects of SPT5 carboxy-terminal phosphorylation on elongation rate are reversed by protein phosphatase 1 (PP1) to facilitate termination. In this review, we summarize the current understanding of the kinase-phosphatase interplay that coordinates steps of the RNAPII transcription cycle to ensure productive mRNA synthesis and cell viability, with a focus on the tripartite phosphorylation of SPT5.

Abstract as supplied by the indexing source. © the authors / publisher.