RNA polymerase II

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Function of RNA polymerase II (transcription). Green: newly synthesized RNA strand by enzyme Label RNA pol II.png
Function of RNA polymerase II (transcription). Green: newly synthesized RNA strand by enzyme

RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. [1] [2] It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. [3] A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

Contents

Discovery

RNA polymerase II of Saccharomyces cerevisiae consisting of all 12 subunits. RNA polymerase II.fcgi.png
RNA polymerase II of Saccharomyces cerevisiae consisting of all 12 subunits.

Early studies suggested a minimum of two RNAPs: one which synthesized rRNA in the nucleolus, and one which synthesized other RNA in the nucleoplasm, part of the nucleus but outside the nucleolus. [5] In 1969, biochemists Robert G. Roeder and William Rutter discovered there are total three distinct nuclear RNA polymerases, an additional RNAP that was responsible for transcription of some kind of RNA in the nucleoplasm. [6] The finding was obtained by the use of ion-exchange chromatography via DEAE coated Sephadex beads. The technique separated the enzymes by the order of the corresponding elutions, Ι,ΙΙ,ΙΙΙ, by increasing the concentration of ammonium sulfate. The enzymes were named according to the order of the elutions, RNAP I, RNAP II, RNAP IΙI. [3] This discovery demonstrated that there was an additional enzyme present in the nucleoplasm, which allowed for the differentiation between RNAP II and RNAP III. [7]

RNA polymerase II (RNAP2) undergoes regulated transcriptional pausing during early elongation. Various studies has shown that disruption of transcription elongation is implicated in cancer, neurodegeneration, HIV latency etc. [8]

Subunits

Eukaryotic RNA-polymerase II from Saccharomyces cerevisiae, PDB ID. Subunits colored: RPB3 - orange , RPB11 - yellow , RPB2 - wheat, RPB1 - red, RPB6 - pink, the rest 7 subunits are colored gray. Eukaryotic RNA-polymerase II structure 1WCM.png
Eukaryotic RNA-polymerase II from Saccharomyces cerevisiae , PDB ID. Subunits colored: RPB3 – orange , RPB11 – yellow , RPB2 – wheat, RPB1 – red, RPB6 – pink, the rest 7 subunits are colored gray.

The eukaryotic core RNA polymerase II was first purified using transcription assays. [10] The purified enzyme has typically 10–12 subunits (12 in humans and yeast) and is incapable of specific promoter recognition. [11] Many subunit-subunit interactions are known. [12]

Assembly

RPB3 is involved in RNA polymerase II assembly. [21] A subcomplex of RPB2 and RPB3 appears soon after subunit synthesis. [21] This complex subsequently interacts with RPB1. [21] RPB3, RPB5, and RPB7 interact with themselves to form homodimers, and RPB3 and RPB5 together are able to contact all of the other RPB subunits, except RPB9. [12] Only RPB1 strongly binds to RPB5. [12] The RPB1 subunit also contacts RPB7, RPB10, and more weakly but most efficiently with RPB8. [12] Once RPB1 enters the complex, other subunits such as RPB5 and RPB7 can enter, where RPB5 binds to RPB6 and RPB8 and RPB3 brings in RPB10, RPB 11, and RPB12. [12] RPB4 and RPB9 may enter once most of the complex is assembled. RPB4 forms a complex with RPB7. [12]

Kinetics

Enzymes can catalyze up to several million reactions per second. Enzyme rates depend on solution conditions and substrate concentration. Like other enzymes POLR2 has a saturation curve and a maximum velocity (Vmax). It has a Km (substrate concentration required for one-half Vmax) and a kcat (the number of substrate molecules handled by one active site per second). The specificity constant is given by kcat/Km. The theoretical maximum for the specificity constant is the diffusion limit of about 108 to 109 (M−1s−1), where every collision of the enzyme with its substrate results in catalysis. In yeast, mutation in the Trigger-Loop domain of the largest subunit can change the kinetics of the enzyme. [22]

Bacterial RNA polymerase, a relative of RNA Polymerase II, switches between inactivated and activated states by translocating back and forth along the DNA. [23] Concentrations of [NTP]eq = 10 μM GTP, 10 μM UTP, 5 μM ATP and 2.5 μM CTP, produce a mean elongation rate, turnover number, of ~1 bp (NTP)−1 for bacterial RNAP, a relative of RNA polymerase II. [23]

RNA Polymerase II gray. Alpha-amanitin interaction (red). Alpha-Amanitin-RNA polymerase II complex 1K83.png
RNA Polymerase II gray. Alpha-amanitin interaction (red).

RNA polymerase II undergoes extensive co-transcriptional pausing during transcription elongation. [24] [25] This pausing is especially pronounced at nucleosomes, and arises in part through the polymerase entering a transcriptionally incompetent backtracked state. [24] The duration of these pauses ranges from seconds to minutes or longer, and exit from long-lived pauses can be promoted by elongation factors such as TFIIS. [26] In turn, the transcription rate influences whether the histones of transcribed nucleosomes are evicted from chromatin, or reinserted behind the transcribing polymerase. [27]

Alpha-Amanitin

RNA polymerase II is inhibited by α-Amanitin [28] and other amatoxins. α-Amanitin is a highly poisonous substance found in many mushrooms. [5] The mushroom poison has different effects on each of the RNA Polymerases: I, II, III. RNAP I is completely unresponsive to the substance and will function normally while RNAP III has a moderate sensitivity. RNAP II, however, is completely inhibited by the toxin. Alpha-Amanitin inhibits RNAP II by strong interactions in the enzyme's "funnel", "cleft", and the key "bridge α-helix" regions of the RPB-1 subunit. [29]

Holoenzyme

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. [11] It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

Part of the assembly of the holoenzyme is referred to as the preinitiation complex, because its assembly takes place on the gene promoter before the initiation of transcription. The mediator complex acts as a bridge between RNA polymerase II and the transcription factors.

Control by chromatin structure

This is an outline of an example mechanism of yeast cells by which chromatin structure and histone post-translational modification help regulate and record the transcription of genes by RNA polymerase II.

This pathway gives examples of regulation at these points of transcription:

This refers to various stages of the process as regulatory steps. It has not been proven that they are used for regulation, but is very likely they are.

RNA Pol II elongation promoters can be summarised in 3 classes.

  1. Drug/sequence-dependent arrest-affected factors (Various interfering proteins)
  2. Chromatin structure-oriented factors (Histone posttranscriptional modifiers, e.g., Histone Methyltransferases)
  3. RNA Pol II catalysis-improving factors (Various interfering proteins and Pol II cofactors; see RNA polymerase II).

Transcription mechanisms

C-terminal Domain

The C-terminus of RPB1 is appended to form the C-terminal domain (CTD). The carboxy-terminal domain of RNA polymerase II typically consists of up to 52 repeats of the sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. [32] The domain stretches from the core of the RNAPII enzyme to the exit channel, this placement is effective due to its inductions of "RNA processing reactions, through direct or indirect interactions with components of the RNA processing machinery". [33] The CTD domain does not exist in RNA Polymerase I or RNA Polymerase III. [3] The RNA Polymerase CTD was discovered first in the laboratory of C. J. Ingles at the University of Toronto and also in the laboratory of J Corden at Johns Hopkins University during the processes of sequencing the DNA encoding the RPB1 subunit of RNA polymerase from yeast and mice respectively. Other proteins often bind the C-terminal domain of RNA polymerase in order to activate polymerase activity. It is the protein domain that is involved in the initiation of transcription, the capping of the RNA transcript, and attachment to the spliceosome for RNA splicing. [13]

Phosphorylation of the CTD

RNA Polymerase II exists in two forms unphosphorylated and phosphorylated, IIA and IIO respectively. [5] [3] The transition between the two forms facilitates different functions for transcription. The phosphorylation of CTD is catalyzed by one of the six general transcription factors, TFIIH. TFIIH serves two purposes: one is to unwind the DNA at the transcription start site and the other is to phosphorylate. The form polymerase IIA joins the preinitiation complex, this is suggested because IIA binds with higher affinity to the TBP (TATA-box binding protein), the subunit of the general transcription factor TFIID, than polymerase IIO form. The form polymerase IIO facilitates the elongation of the RNA chain. [5] The method for the elongation initiation is done by the phosphorylation of serine at position 5 (Ser5), via TFIIH. The newly phosphorylated Ser5 recruits enzymes to cap the 5' end of the newly synthesized RNA and the "3' processing factors to poly(A) sites". [33] Once the second serine is phosphorylated, Ser2, elongation is activated. In order to terminate elongation dephosphorylation must occur. Once the domain is completely dephosphorylated the RNAP II enzyme is "recycled" and catalyzes the same process with another initiation site. [33]

Transcription coupled recombinational repair

Oxidative DNA damage may block RNA polymerase II transcription and cause strand breaks. An RNA templated transcription-associated recombination process has been described that can protect against DNA damage. [34] During the G1/G0 stages of the cell cycle, cells exhibit assembly of homologous recombination factors at double-strand breaks within actively transcribed regions. It appears that transcription is coupled to repair of DNA double-strand breaks by RNA templated homologous recombination. This repair process efficiently and accurately rejoins double-strand breaks in genes being actively transcribed by RNA polymerase II.

See also

Related Research Articles

<span class="mw-page-title-main">Polymerase</span> Class of enzymes which synthesize nucleic acid chains or polymers

In biochemistry, a polymerase is an enzyme that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base-pairing interactions or RNA by half ladder replication.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">RNA polymerase</span> Enzyme that synthesizes RNA from DNA

In molecular biology, RNA polymerase, or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template.

In genetics, a transcription terminator is a section of nucleic acid sequence that marks the end of a gene or operon in genomic DNA during transcription. This sequence mediates transcriptional termination by providing signals in the newly synthesized transcript RNA that trigger processes which release the transcript RNA from the transcriptional complex. These processes include the direct interaction of the mRNA secondary structure with the complex and/or the indirect activities of recruited termination factors. Release of the transcriptional complex frees RNA polymerase and related transcriptional machinery to begin transcription of new mRNAs.

<span class="mw-page-title-main">Transcription preinitiation complex</span> Complex of proteins necessary for gene transcription in eukaryotes and archaea

The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.

RNA polymerase 1 is, in higher eukaryotes, the polymerase that only transcribes ribosomal RNA, a type of RNA that accounts for over 50% of the total RNA synthesized in a cell.

<span class="mw-page-title-main">General transcription factor</span> Class of protein transcription factors

General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (promoter) on DNA to activate transcription of genetic information from DNA to messenger RNA. GTFs, RNA polymerase, and the mediator constitute the basic transcriptional apparatus that first bind to the promoter, then start transcription. GTFs are also intimately involved in the process of gene regulation, and most are required for life.

<span class="mw-page-title-main">Capping enzyme</span>

A capping enzyme (CE) is an enzyme that catalyzes the attachment of the 5' cap to messenger RNA molecules that are in the process of being synthesized in the cell nucleus during the first stages of gene expression. The addition of the cap occurs co-transcriptionally, after the growing RNA molecule contains as little as 25 nucleotides. The enzymatic reaction is catalyzed specifically by the phosphorylated carboxyl-terminal domain (CTD) of RNA polymerase II. The 5' cap is therefore specific to RNAs synthesized by this polymerase rather than those synthesized by RNA polymerase I or RNA polymerase III. Pre-mRNA undergoes a series of modifications - 5' capping, splicing and 3' polyadenylation before becoming mature mRNA that exits the nucleus to be translated into functional proteins and capping of the 5' end is the first of these modifications. Three enzymes, RNA triphosphatase, guanylyltransferase, and methyltransferase are involved in the addition of the methylated 5' cap to the mRNA.

Cleavage and polyadenylation specificity factor (CPSF) is involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription. In eukaryotes, messenger RNA precursors (pre-mRNA) are transcribed in the nucleus from DNA by the enzyme, RNA polymerase II. The pre-mRNA must undergo post-transcriptional modifications, forming mature RNA (mRNA), before they can be transported into the cytoplasm for translation into proteins. The post-transcriptional modifications are: the addition of a 5' m7G cap, splicing of intronic sequences, and 3' cleavage and polyadenylation.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

<span class="mw-page-title-main">POLR2A</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase II subunit RPB1, also known as RPB1, is an enzyme that is encoded by the POLR2A gene in humans.

<span class="mw-page-title-main">RNA polymerase II subunit B4</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase II subunit RPB4 is an enzyme that in humans is encoded by the POLR2D gene.

<span class="mw-page-title-main">GTF2H1</span> Protein-coding gene in the species Homo sapiens

General transcription factor IIH subunit 1 is a protein that in humans is encoded by the GTF2H1 gene.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

<span class="mw-page-title-main">DSIF</span>

DSIF is a protein complex that can either negatively or positively affect transcription by RNA polymerase II. It can interact with the negative elongation factor (NELF) to promote the stalling of Pol II at some genes, which is called promoter proximal pausing. The pause occurs soon after initiation, once 20-60 nucleotides have been transcribed. This stalling is relieved by positive transcription elongation factor b (P-TEFb) and Pol II enters productive elongation to resume synthesis till finish. In humans, DSIF is composed of hSPT4 and hSPT5. hSPT5 has a direct role in mRNA capping which occurs while the elongation is paused.

RNA polymerase IV is an enzyme that synthesizes small interfering RNA (siRNA) in plants, which silence gene expression. RNAP IV belongs to a family of enzymes that catalyze the process of transcription known as RNA Polymerases, which synthesize RNA from DNA templates. Discovered via phylogenetic studies of land plants, genes of RNAP IV are thought to have resulted from multistep evolution processes that occurred in RNA Polymerase II phylogenies. Such an evolutionary pathway is supported by the fact that RNAP IV is composed of 12 protein subunits that are either similar or identical to RNA polymerase II, and is specific to plant genomes. Via its synthesis of siRNA, RNAP IV is involved in regulation of heterochromatin formation in a process known as RNA directed DNA Methylation (RdDM).

Cryptic unstable transcripts (CUTs) are a subset of non-coding RNAs (ncRNAs) that are produced from intergenic and intragenic regions. CUTs were first observed in S. cerevisiae yeast models and are found in most eukaryotes. Some basic characteristics of CUTs include a length of around 200–800 base pairs, a 5' cap, poly-adenylated tail, and rapid degradation due to the combined activity of poly-adenylating polymerases and exosome complexes. CUT transcription occurs through RNA Polymerase II and initiates from nucleosome-depleted regions, often in an antisense orientation. To date, CUTs have a relatively uncharacterized function but have been implicated in a number of putative gene regulation and silencing pathways. Thousands of loci leading to the generation of CUTs have been described in the yeast genome. Additionally, stable uncharacterized transcripts, or SUTs, have also been detected in cells and bear many similarities to CUTs but are not degraded through the same pathways.

RNA polymerase V, previously known as RNA polymerase IVb, is a multisubunit plant specific RNA polymerase. It is required for normal function and biogenesis of small interfering RNA (siRNA). Together with RNA polymerase IV, Pol V is involved in an siRNA-dependent epigenetic pathway known as RNA-directed DNA methylation (RdDM), which establishes and maintains heterochromatic silencing in plants.

In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

<span class="mw-page-title-main">Archaeal transcription</span>

Archaeal transcription is the process in which a segment of archaeal DNA is copied into a newly synthesized strand of RNA using the sole Pol II-like RNA polymerase (RNAP). The process occurs in three main steps: initiation, elongation, and termination; and the end result is a strand of RNA that is complementary to a single strand of DNA. A number of transcription factors govern this process with homologs in both bacteria and eukaryotes, with the core machinery more similar to eukaryotic transcription.

References

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