- RNA Polymerase III (Pol III) is a specialized eukaryotic enzyme responsible for transcribing small, structured, non-coding RNAs that are essential for basic cellular functions. These include transfer RNAs (tRNAs), 5S ribosomal RNA (rRNA), U6 small nuclear RNA (snRNA), and various other small RNAs involved in RNA processing, splicing, and regulatory activities. Pol III operates predominantly in the nucleus and plays a crucial role in maintaining the translational capacity and RNA-based regulatory mechanisms of the cell.
- Structurally, RNA Polymerase III is a multi-subunit complex composed of 17 subunits, sharing some homologous components with RNA Polymerases I and II, but also containing unique subunits that confer specificity for its distinct set of target genes. The enzyme is large and complex, reflecting its involvement in synthesizing RNAs with intricate secondary structures and in maintaining tight control over the production of these molecules, which are often present in high copy numbers.
- Transcription by Pol III differs from that of RNA Polymerase II in its promoter recognition and transcription factor requirements. Pol III transcribes genes that often contain internal promoters, particularly in the case of tRNA and 5S rRNA genes. These internal promoters are located within the transcribed region itself. For example, tRNA genes possess two highly conserved promoter elements, Box A and Box B, within the coding sequence. Transcription initiation involves the binding of specialized transcription factors—TFIIIC recognizes the internal promoter elements and recruits TFIIIB, which then recruits Pol III to the transcription start site. In contrast, for some genes like U6 snRNA, external promoter elements and additional transcription factors such as SNAPc are involved.
- Once recruited, RNA Polymerase III initiates transcription and rapidly transitions into elongation, synthesizing RNA in a 5′ to 3′ direction. The transcripts produced by Pol III are typically short and structurally stable, often folding into functional conformations immediately upon synthesis. Because many Pol III-transcribed genes are needed in large quantities, this polymerase is optimized for high initiation frequency and transcriptional throughput.
- Termination of Pol III transcription is unique and relatively simple, relying on a stretch of thymidine residues (poly-T) in the DNA template. This sequence is recognized without the need for additional termination factors, causing Pol III to pause and release the RNA transcript. The simplicity of this mechanism allows for efficient recycling of the polymerase and supports high levels of transcriptional output.
- Pol III activity is tightly regulated by cellular conditions and signaling pathways. Under growth-promoting conditions, such as nutrient availability and mitogenic stimulation, Pol III activity is upregulated via the mTOR signaling pathway and oncogenes like c-Myc. In contrast, cellular stress, nutrient deprivation, or differentiation signals often lead to repression of Pol III activity, primarily through the action of tumor suppressor proteins such as p53 and RB, which can interfere with the assembly of Pol III transcription complexes.
