Transcription termination and the control of the transcriptome: why, where and how to stop

Abstract

Transcription termination occurs when the polymerase is released after a transcription event, thus delimitating transcription units; however, the functional importance of termination extends beyond the mere definition of gene borders. By determining the cellular fate of the generated transcripts, transcription termination pathways shape the transcriptome. Recent reports have underscored the crucial role of these pathways in limiting the extent of pervasive transcription, which has attracted interest in post-initiation events in gene expression control. Transcription termination pathways involved in the production of non-coding RNAs - such as the Nrd1-Nab3-Sen1 (NNS) pathway in yeast and the cap-binding complex (CBC)-ARS2 pathway in humans - are key determinants of transcription quality control. Understanding the mechanisms leading to the timely and efficient dismantling of elongation complexes remains a major unmet challenge, but new insights into the molecular basis of termination at mRNA-coding and non-coding RNA gene targets have been gained in eukaryotes.

Divergence of a conserved elongation factor and transcription regulation in budding and fission yeast

“…In contrast, the majority of genes in metazoans, including mammals and flies, are intricately regulated at a promoter-proximal pausing step during elongation (Fuda et al 2009;Adelman and Lis 2012). Characteristics of transcription elongation also differ between metazoans and S. cerevisiae beyond the cleavage and polyadenylation signal (CPS) (Porrua and Libri 2015). In contrast to budding yeast, elongating Pol II in mammals experiences post-CPS slowing or pausing while continuing to transcribe for several kilobases prior to termination (Proudfoot 1989;Gromak et al 2006;Core et al 2008;Laitem et al 2015).…”

Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

“…In the case of non‐coding RNAs, such as cryptic unstable transcripts (CUTs) and small nucleolar RNAs (snoRNAs), Pol II terminates transcription via a non‐canonical pathway that is coupled to RNA degradation (reviewed in Jensen et al , 2013). This non‐canonical termination pathway depends on the Nrd1‐Nab3‐Sen1 (NNS) complex (reviewed in Arndt & Reines, 2015; Porrua & Libri, 2015a). Nrd1 and Nab3 form a heterodimer (Carroll et al , 2007) that underpins the substrate specificity of the NNS complex (Wlotzka et al , 2011; Porrua et al , 2012; Schulz et al , 2013).…”

Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

“…While the two yeast Pol II termination pathways generally operate on distinct sets of transcripts, there are some genes that can use either termination pathway (11). In some cases NNS acts downstream of genes as a fail-safe termination mechanism to ensure that transcripts that fail to terminate through the cleavage/polyadenylation mechanism do not read through into downstream genes (34,35).…”

“…Both coding and noncoding transcripts originate from promoters located in nucleosome-free regions in a process that requires both general transcription factors and gene-specific factors (5-7), but termination of these different classes of Pol II transcripts takes place through two different processes. Stable transcripts like mRNA and SUTs terminate through a process linked to cleavage and polyadenylation while snoRNAs and CUTs terminate through the Nrd1-Nab3-Sen1 (NNS) pathway (8)(9)(10)(11)(12)(13)(14).…”

“…Both coding and noncoding transcripts originate from promoters located in nucleosome-free regions in a process that requires both general transcription factors and gene-specific factors (5-7), but termination of these different classes of Pol II transcripts takes place through two different processes. Stable transcripts like mRNA and SUTs terminate through a process linked to cleavage and polyadenylation while snoRNAs and CUTs terminate through the Nrd1-Nab3-Sen1 (NNS) pathway (8)(9)(10)(11)(12)(13)(14).The NNS complex contains two RNA-binding proteins, Nrd1 and Nab3, which recognize specific sequences in nascent transcripts and direct termination in a process that requires the RNA helicase Sen1 (8,9,(15)(16)(17)(18)(19)(20). NNS interacts with Pol II in part through binding of Nrd1 to phosphorylated Ser5 on the C-terminal domain (CTD) (21-23), a pattern of CTD phosphorylation most prominent in the early stages of the transcription cycle, limiting NNS termination to promoter-proximal transcripts (24-29).…”