Unravelling the means to an end: RNA polymerase II transcription termination

• Published in: Nature reviews. Molecular cell biology Vol. 12; no. 5; pp. 283 - 294
• Main Authors: Moore, Claire, Kuehner, Jason N, Pearson, Erika L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2011; Nature Publishing Group
• Subjects: 631/208/200; 631/337/572; Animals; Biochemistry; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Gene expression; Genetic transcription; Genomes; Humans; Life Sciences; Models, Genetic; Physiological aspects; Poly A - genetics; Protein Binding; Proteins; review-article; RNA; RNA polymerase; RNA Polymerase II - metabolism; RNA polymerases; RNA, Messenger - genetics; Stem Cells; Synthesis; Transcription Factors - metabolism; Transcription, Genetic - genetics; United States
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm3098

Key Points
RNA polymerase II (Pol II) transcribes all eukaryotic protein-coding genes and most non-coding RNA genes. The final step of transcription is termination, which leads to the release of Pol II and RNA from the DNA template through a poorly defined mechanism.
Transcription termination serves many vital functions in the cell, such as preventing RNA polymerase interference with neighbouring DNA elements, recycling RNA polymerase, promoting RNA 3′-end processing, and regulating gene expression via premature termination of transcription (that is, attenuation).
Termination can be elicited through different pathways depending on the phosphorylation status of the Pol II carboxy-terminal domain (CTD) and the presence of various RNA signals and termination factors. Two of the best-studied termination pathways are the poly(A)-dependent pathway and Sen1-dependent pathway, which are connected to RNA 3′-end processing events for mRNAs and non-coding RNAs, respectively.
Three mechanisms are proposed to cause Pol II termination: conformational changes induced by binding of factors to Pol II; collision of an exoribonuclease with Pol II; and/or disruption of the Pol II active site hybrid by an RNA–DNA helicase. However, these molecular models have thus far remained insufficient to fully explain how termination occurs.
Pol II is similar both structurally and biochemically to bacterial RNA polymerase, suggesting that there may be some general features of termination that are common to all cellular RNA polymerases. Recent studies investigating the requirements for bacterial termination implicate several regions of Pol II as putative termination effector domains, including the lid, trigger loop, clamp helices, dock and flap.
The phosphorylation status of the Pol II CTD residues Ser
7
, Ser
5
and Ser
2
is dynamic across the length of a gene. Genome-wide localization studies suggest that a combination of high Ser7-P and Ser5-P and low Ser2-P in the CTD of Pol II at promoter-proximal positions may serve as a signal to trigger Sen1-dependent termination.
Genome-wide localization of protein 1 of CFI (Pcf11), Nrd1, and RNA-trafficking protein 1 (Rat1) reveals extensive overlap of these termination factors along both protein-coding and non-coding RNA genes. This pattern is consistent with the idea that the machinery for Sen1-dependent termination and poly(A)-dependent termination is broadly available to target Pol II during transcription of most genes, and in fact may provide a way to ensure fail-safe termination.
Transcription termination is one of the least-understood processes in gene expression. However, recent studies have revealed common themes and principles between models of RNA polymerase II (Pol II) termination, including the poly(A)-dependent and Sen1-dependent pathways, and provided insight into the role of Pol II carboxy-terminal domain phosphorylation in this process.
The pervasiveness of RNA synthesis in eukaryotes is largely the result of RNA polymerase II (Pol II)-mediated transcription, and termination of its activity is necessary to partition the genome and maintain the proper expression of neighbouring genes. Despite its ever-increasing biological significance, transcription termination remains one of the least understood processes in gene expression. However, recent mechanistic studies have revealed a striking convergence among several overlapping models of termination, including the poly(A)- and Sen1-dependent pathways, as well as new insights into the specificity of Pol II termination among its diverse gene targets. Broader knowledge of the role of Pol II carboxy-terminal domain phosphorylation in promoting alternative mechanisms of termination has also been gained.