id: PW:0000128 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000128 title: rna polymerase iii transcription pathway description: The three eukaryotic RNA polymerases (RNAPs)- Pol I, II and III, transcribe different sets of genes and require distinct sets of factors to assemble a specific initiation complex which recruits them on gene promoters. The multi-subunit enzymes are composed of 14 (RNAPI), 12 (RNAPII) and 17 (RNAPIII) subunits of which some are shared and others are unique, yet converging on an overall similar structural topology. Complexes specific to each of the three systems share the universal transcription factor 'TATA-box binding protein' (TBP) regardless of whether the promoters have a TATA box or not. In addition, modules and domains present in general transcription factors (GTFs) specific for RNAPII are found in subunits of RNAPI and RNAPIII and/or RNAPI and RNAPIII specific factors. The initiation, elongation and termination of transcription are steps shared by all systems, albeit with differing details and/or degrees of complexity. Beyond the shared or related elements, specific factors confer unique topological and functional features to the particular initiation complex associated with the three polymerases and account for the differences in promoter recognition and the class or category of transcribed genes. Pol I transcribes ribosomal RNA, all protein-coding and many non-coding genes are transcribed by pol II, while transfer RNA (tRNA), the small 5S ribosomal RNA (5SrRNA) and a subset of small non-coding genes are the realm of pol III mediated transcription. Transcription by RNA pol III is described here. RNA polymerase III transcription pathway Pol III is responsible for the transcription of all tRNA, the small ribosomal 5SrRNA and several other non-coding RNAs including U6 spliceosomal RNA, vault and Y RNAs. Largely, pol III promoters are characterized by the presence of internal elements downstream of the transcription start site (TSS). This is the case for type I and type II promoters involved in the transcription of 5S ribosomal RNA (5SrRNA) and of transfer RNA (tRNA) genes, respectively. Type I promoters exhibit an internal/intermediate element (IE) and the C box, recognized by the transcription factor IIIA (TFIIIA) which then recruits the multi-subunit transcription factor IIIC (TFIIIC). Type II promoters have the two, highly conserved A and B boxes, directly recognized by TFIIIC. TFIIIC is responsible for recruiting the core pol III transcription factor IIIB (TFIIIB) upstream of the transcription start site (TSS), which then recruits the polymerase. A type III promoter is only present in vertebrates, has a canonical TATA box and an upstream proximal sequence element (PSE), recognized by the multi-subunit SNAPc binding factor (small nuclear RNA activating protein complex), also known as PBP or PTF. Upstream factors, such as Pou2f1 (Oct-1) or Zfp143 (Staf), bound to distal promoter element (DSE), reinforce the interaction of SNAPc with PSE. Cooperative binding of SNAPc and TFIIIB to PSE and TATA box, respectively, results in Pol III recruitment. TFIIIA, which binds both the 5S rRNA gene promoter and 5S RNA itself, has nine archetypal zinc-finger motifs underlying the DNA and RNA recognition versatility and specificity. TFIIIC consists of six subunits GTF3C1-to-C6, in turn part of two sub-complexes ¿ tA and tB binding to the A and B box, respectively. By comparison with yeast, where many pol II studies have been carried out, the human tB sub-complex consists of GTF3C1, 2 and 4 and the tA sub-complex, of GTF3C3, 5 and 6. Despite the central role of TFIIIC in transcription from type I and II promoters, the molecular mechanisms of both transcription and the reported extra-transcriptional activity, remain to be elucidated. The upstream SNAPc is composed of five subunits SNAPC1-to-C5. The core TFIIIB is composed of TBP, Bdp1 and either Brf1 in type I and II promoters, or Brf2 in type III promoters. The N-terminus of Brf1 and 2 has homology to TFIIB, the core pol II transcription factor while the C-terminus interacts with TBP, pol III and Bdp1. Despite a low sequence homology, both the yeast and human Bdp1 proteins possess a SANT domain responsible for the interaction with Brf1/2. The three forms of human BDP1, arising from alternative splicing, all preserve the SANT domain. Once recruited, pol III and GTFs are part of a preinitiation complex (PIC) which transitions from a closed to the transcription-prone conformation. Pol III, with 17 subunits, is the largest of the three eukaryotic polymerases. Of these, five are shared with pol I and II and additional two, with pol I. The remaining are pol III specific; the two largest form the active center and nucleic acid binding cleft, other two form the stalk structure, one subunit performs RNA cleavage during backtracking and the remaining five form one heterodimer and one heterotrimer. The heterodimer is distantly related to pol II TFIIF and plays a role in all stages of pol III transcription, the heterotrimer is distantly related to pol II TFIIE and plays a role in transcription initiation. Subunits within the trimer contain winged-helix (WH) domains and this, along with coordinated contributions from heterodimer domains and TFIIIB, underlie the opening of PIC and melting of DNA, which in contrast to pol II, does not require energy. Once transcription is initiated, the elongation step does not require additional factors. Conformational changes in pol III subsequent to binding the transcription bubble, particularly in the specific sub-complexes, are thought to increase the processivity of the enzyme. The presence of several thymidine (T) residues on the non-template (coding) strand, represents the termination signal, an event in which the heterodimeric pol III sub-complex plays an important role. Reinitiation of transcription (several rounds of transcription on the same gene), also referred to as facilitated recycling, is a distinguishing feature of pol III system with TFIIIB playing an important role. The chromatin associated protein Sub1, with multiple roles in gene expression, acts as a reinitiation factor - it interacts with components of TFIIIB and TFIIIC upon which it exerts a stabilizing effect and is able to bend DNA. Pol III subunits are involved in termination and the coupling of termination and reinitiation. Other factors may also contribute to reinitiation, but their role awaits further investigation. Several repression systems regulate pol III transcription system of which Maf1 is an essential regulator whose interaction with pol III and the Brf1 component of TFIIIIB preclude de novo assembly of transcription complex. Under normal conditions, Maf1 is phosphorylated and resides in the cytoplasm; stresses lead to its dephosphorylation and import into the nucleus where it represses pol III. Human MAF1 may be a substrate of mTorc1 kinase complex of mTOR signaling pathway. The retinoblastoma tumor suppressor Rb1 globally inhibits pol III transcription via association with TFIIIB-Brf1 for type II promoter loci and with components of SNAPc for type III loci. Maturation of tRNA includes removal of 5' leader, of 3' trailer and addition of CCA, splicing of intron containing genes and the myriad modifications whose function is still to be elucidated. Unlike the maturation of other RNA transcripts, which largely occurs cotranscriptionally, tRNA processing, as seen in the yeast system, takes place in many compartments. diagram_image: https://rgd.mcw.edu/pathway/PW0000128/RNA%20polymerase%20III%20transcription%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000128/RNA%20polymerase%20III%20transcription%20pathway/RNA%20polymerase%20III%20transcription%20pathway.gpp diagram_pathway_links: - id: PW:0000180 label: mTOR signaling pathway - id: PW:0001337 label: chromatin modification/remodeling pathway - id: PW:0001573 label: tRNA maturation pathway diagram_gene_links: - id: RGD:1359315 label: Maf1 - id: RGD:621689 label: Pou2f1 - id: RGD:3540 label: Rb1 - id: RGD:621582 label: Sub1 - id: RGD:619746 label: TFIIIA - id: RGD:1305662 label: Zfp143 diagram_chemicals: [] diagram_edges: - source: Maf1 relation: associated_with target: RNA polymerase III - source: Maf1 relation: associated_with target: TFIIIB - source: Maf1 relation: negatively_affects target: RNA polymerase III - source: Maf1 relation: negatively_affects target: TFIIIB - source: RNA polymerase III relation: associated_with target: TFIIIB - source: RNA polymerase III relation: positively_affects target: pre-tRNA transcript - source: Rb1 relation: associated_with target: SNAPc - source: Rb1 relation: associated_with target: TFIIIB - source: Rb1 relation: negatively_affects target: SNAPc - source: Rb1 relation: negatively_affects target: TFIIIB - source: SNAPc relation: associated_with target: TFIIIB - source: Sub1 relation: associated_with target: TFIIIB - source: Sub1 relation: associated_with target: TFIIIC - source: TFIIIA relation: associated_with target: TFIIIC - source: TFIIIB relation: associated_with target: TFIIIC - source: mTOR signaling pathway relation: negatively_affects target: Maf1 diagram_labels: - Pou2f1 --+> SNAPc - pre-tRNA transcript - stress - stress --+> Maf1 - Zfp143 --+> SNAPc diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/rna-polymerase-iii label: RNA polymerase III - href: /wg/home/pathway2/molecular-pathways2/snapc label: SNAPc - href: /wg/home/pathway2/molecular-pathways2/tfiiib label: TFIIIB - href: /wg/home/pathway2/molecular-pathways2/tfiiic label: TFIIIC references: - id: RGD:9588284 citation: 'Vannini A Biochim Biophys Acta. 2013 Mar-Apr;1829(3-4):258-64. doi: 10.1016/j.bbagrm.2012.09.009. 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