POLR2A

Official Full Name

RNA polymerase II subunit A

Organism

Homo sapiens

GeneID

5430

Background

This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

Synonyms

RPB1; RPO2; POLR2; POLRA; RPBh1; RPOL2; NEDHIB; RpIILS; hsRPB1; hRPB220;

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Detailed Information

The POLR2A gene encodes the largest catalytic subunit of RNA polymerase II, RPB1, exemplifying a core executor of gene function. Located on human chromosome 17p13.1, POLR2A is one of twelve subunits comprising RNA polymerase II, forming the central catalytic core of the enzyme. RNA polymerase II is the essential molecular machinery in eukaryotes responsible for transcribing all precursor messenger RNAs, most small RNAs, and long non-coding RNAs, underscoring POLR2A's critical role in maintaining fundamental cellular functions.

Structurally, POLR2A is notable for its unique C-terminal domain (CTD), consisting of 52 tandem repeats of the heptapeptide sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. Although the CTD does not participate in catalysis directly, it serves as a dynamic regulatory platform. During different stages of the transcription cycle, serine and threonine residues within the CTD undergo complex post-translational modifications-including phosphorylation, acetylation, and methylation-which act as "signals" to recruit transcription factors, RNA processing proteins, and histone-modifying enzymes, coordinating transcription initiation, elongation, termination, and co-transcriptional RNA processing.

Biological Significance

POLR2A's biological significance stems from its role as the central engine of eukaryotic transcription. It catalyzes RNA synthesis using DNA as a template and ribonucleotide triphosphates as substrates, coordinating two magnesium ions at the catalytic center to extend the RNA chain nucleotide by nucleotide. The transcription cycle is tightly regulated: during initiation, POLR2A forms a pre-initiation complex with general transcription factors at gene promoters; after promoter escape, it enters elongation, synthesizing the RNA transcript along the DNA template; and finally, it terminates transcription at gene ends.

Figure 1. Disassociated RPB3 preferentially regulates 3′ end processing of ribosomal subunit genes. (Li Y, et al., 2023)

The CTD functions as a regulatory hub: phosphorylation of serine-5 recruits capping enzymes during transcription initiation, whereas phosphorylation of serine-2 correlates with elongation, RNA splicing, and 3′-end polyadenylation. POLR2A also has intrinsic proofreading activity, removing misincorporated nucleotides via a 3′→5′ exonuclease-like mechanism, ensuring relative transcriptional fidelity. Recent studies indicate POLR2A may occasionally act as an RNA-guided RNA polymerase, extending certain non-coding RNAs, potentially contributing to regulatory circuits. Its expression is tightly controlled; haploinsufficiency is lethal in multiple cell types. Moreover, some viruses, such as the hepatitis D virus, exploit POLR2A by converting host DNA-dependent RNA polymerase II into an RNA-dependent polymerase to replicate viral RNA genomes.

Clinical Relevance

POLR2A's clinical importance manifests in two areas: as a potential vulnerability in certain cancers and as a cause of neurodevelopmental disorders. In oncology, POLR2A is adjacent to the tumor suppressor TP53 on chromosome 17p. Many cancers harbor heterozygous TP53 deletions, placing POLR2A in a haploinsufficient state. Since POLR2A is essential for cell survival, further reduction of its expression or activity selectively kills these cancer cells while sparing normal cells. For example, low doses of α-amanitin or related RNA polymerase II inhibitors preferentially inhibit tumor cells with POLR2A haploinsufficiency, presenting a targeted therapeutic approach for TP53/POLR2A co-deleted cancers.

In neurodevelopment, de novo heterozygous POLR2A variants cause POLR2A-related neurodevelopmental syndrome. These gain-of-function or dominant-negative mutations impair RNA polymerase II assembly or function, thereby disrupting global transcription programs that are critical for brain development. Affected individuals present with intellectual disability, developmental delay, hypotonia, and craniofacial anomalies, highlighting the necessity of precise POLR2A regulation for normal neurological development.

POLR2A is also a target for natural toxins and pharmacological agents, making its study central to understanding transcription regulation and developing therapies for transcription-dependent diseases and viral infections.

References

Bao L, Zhu J, Shi T, Jiang Y, et al. Increased transcriptional elongation and RNA stability of GPCR ligand binding genes unveiled via RNA polymerase II degradation. Nucleic Acids Res. 2024 Aug 12;52(14):8165-8183.
Nagy-Mikó B, Németh-Szatmári O, Faragó-Mészáros R, et al. Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure. Int J Mol Sci. 2023 Nov 1;24(21):15869.
Dwianingsih EK, Krisnugraha YP, Bawono RG, et al. Molecular biomarkers in meningioma (Review). Biomed Rep. 2025 Jan 30;22(4):56.
Muñoz JC, Beckerman I, Choudhary R, et al. DNA Damage-Induced RNAPII Degradation and Its Consequences in Gene Expression. Genes (Basel). 2022 Oct 26;13(11):1951.
Li Y, Huang J, Bao L, et al. RNA Pol II preferentially regulates ribosomal protein expression by trapping disassociated subunits. Mol Cell. 2023 Apr 20;83(8):1280-1297.e11.

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