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Review
. 2024 Feb 1;14(2):176.
doi: 10.3390/biom14020176.

Mechanisms and Functions of the RNA Polymerase II General Transcription Machinery during the Transcription Cycle

Stephen R Archuleta  1 , James A Goodrich  1 , Jennifer F Kugel  1
Affiliations
Review

Mechanisms and Functions of the RNA Polymerase II General Transcription Machinery during the Transcription Cycle

Stephen R Archuleta et al. Biomolecules. .

Abstract

Central to the development and survival of all organisms is the regulation of gene expression, which begins with the process of transcription catalyzed by RNA polymerases. During transcription of protein-coding genes, the general transcription factors (GTFs) work alongside RNA polymerase II (Pol II) to assemble the preinitiation complex at the transcription start site, open the promoter DNA, initiate synthesis of the nascent messenger RNA, transition to productive elongation, and ultimately terminate transcription. Through these different stages of transcription, Pol II is dynamically phosphorylated at the C-terminal tail of its largest subunit, serving as a control mechanism for Pol II elongation and a signaling/binding platform for co-transcriptional factors. The large number of core protein factors participating in the fundamental steps of transcription add dense layers of regulation that contribute to the complexity of temporal and spatial control of gene expression within any given cell type. The Pol II transcription system is highly conserved across different levels of eukaryotes; however, most of the information here will focus on the human Pol II system. This review walks through various stages of transcription, from preinitiation complex assembly to termination, highlighting the functions and mechanisms of the core machinery that participates in each stage.

Keywords: RNA polymerase II (Pol II); general transcription factors (GTFs); preinitiation complex; promoter; transcription.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Phosphorylation state of the Pol II CTD is regulated during transcription. As Pol II transcribes through a gene and progresses through the stages of transcription (shown from left to right), different phosphorylation marks are added or removed to promote unique functions. The phosphorylation patterns shown here pertain to human Pol II; other organisms may exhibit slight differences in these patterns. TSS, transcription start site; PAS, polyadenylation site.
Figure 2
Figure 2
Two mechanisms for PIC formation, which are not mutually exclusive. (a) In the stepwise model, Pol II and the GTFs assemble in a particular order facilitated by one factor recruiting the subsequent factor via protein–protein interactions. (b) In the holoenzyme model, minimally TFIID and TFIIA assemble at the promoter while Pol II and remaining GTFs form a subcomplex that binds to the promoter, completing PIC assembly.
Figure 3
Figure 3
Promoter proximal pausing mechanism of Pol II. Around 30–100 bases downstream of the TSS, Pol II pauses transcription due to the recruitment (blue arrow) of NELF and DSIF (Spt4 and Spt5) (1). Pausing is released when P-TEFb is recruited (blue arrow), Spt5 and NELF are phosphorylated by the CDK9 subunit of P-TEFb, and NELF dissociates (gray arrow) (2). As Pol II transitions to productive elongation, elongation factors (EFs) are recruited (blue arrow), thereby increasing Pol II elongation efficiency (green arrow) (3).
Figure 4
Figure 4
Pol II requires a complex network of factors to facilitate termination. Pol II transcribes through the gene body at over 2 kilobases per minute (1). Subunits in the CPA complex recognize the PAS in the transcript RNA, along with other regulatory sequences. The CPSF73 endonuclease subunit cleaves the nascent RNA to generate the 3′ end of the mRNA, which undergoes further processing such as addition of up to several hundred adenosine residues to the 3′ end of the cleaved mRNA by polyA polymerase (2). PP1/PNUTS dephosphorylates the Spt5 subunit of DSIF (gray arrow), which causes Pol II to decelerate (3). The XRN2 exonuclease binds to the 5′ end of the nascent transcript, digesting it until it until Pol II is dislodged from the genome (4).
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