DNA-directed RNA polymerase I subunit RPA1

Function

Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Transcribes 47S pre-rRNAs from multicopy rRNA gene clusters, giving rise to 5.8S, 18S and 28S ribosomal RNAs. Pol I-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol I pre-initiation complex (PIC) is recruited by the selectivity factor 1 (SL1/TIF-IB) complex bound to the core promoter that precedes an rDNA repeat unit. The PIC assembly bends the promoter favoring the formation of the transcription bubble and promoter escape. Once the polymerase has escaped from the promoter it enters the elongation phase during which RNA is actively polymerized, based on complementarity with the template DNA strand. Highly processive, assembles in structures referred to as 'Miller trees' where many elongating Pol I complexes queue and transcribe the same rDNA coding regions. At terminator sequences downstream of the rDNA gene, PTRF interacts with Pol I and halts Pol I transcription leading to the release of the RNA transcript and polymerase from the DNA. Forms Pol I active center together with the second largest subunit POLR1B/RPA2. Appends one nucleotide at a time to the 3' end of the nascent RNA, with POLR1A/RPA1 contributing a Mg(2+)-coordinating DxDGD motif, and POLR1B/RPA2 participating in the coordination of a second Mg(2+) ion and providing lysine residues believed to facilitate Watson-Crick base pairing between the incoming nucleotide and the template base. Typically, Mg(2+) ions direct a 5' nucleoside triphosphate to form a phosphodiester bond with the 3' hydroxyl of the preceding nucleotide of the nascent RNA, with the elimination of pyrophosphate. Has proofreading activity: Pauses and backtracks to allow the cleavage of a missincorporated nucleotide via POLR1H/RPA12. High Pol I processivity is associated with decreased transcription fidelity (By similarity).

Classification

Family (Pfam)

PF04997 RNA_pol_Rpb1_1, PF00623 RNA_pol_Rpb1_2, PF04983 RNA_pol_Rpb1_3, PF05000 RNA_pol_Rpb1_4, PF04998 RNA_pol_Rpb1_5

InterPro

DNA-dir_RNA_pol1_lsu_C, DNA-dir_RNA_pol1_lsu_N, DNA-dir_RpoC_beta_prime, RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_1, RNA_pol_Rpb1_3, RNA_pol_Rpb1_3_sf, RNA_pol_Rpb1_4, RNA_pol_Rpb1_5, RNA_pol_Rpb1_clamp_domain, Rpb1_funnel_sf

Functional cluster

Central Metabolic Enzymes (KARI/Glycolysis)

Experimental structures · PDB · 7

• 7OB9 EM 2.70A
• 7OBA EM 3.10A
• 7OBB EM 3.30A
• 7VBA EM 2.89A
• 7VBB EM 2.81A
• 7VBC EM 3.01A
• 8A43 EM 4.09A

A predicted model is available from AlphaFold.

Gene Ontology · 18

• GO:0000785 chromatin
• GO:0005694 chromosome
• GO:0001650 fibrillar center
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005736 RNA polymerase I complex
• GO:0003682 chromatin binding
• GO:0003677 DNA binding
• GO:0003899 DNA-directed RNA polymerase activity
• GO:0071667 DNA/RNA hybrid binding
• GO:0000287 magnesium ion binding
• GO:0008270 zinc ion binding
• GO:1904750 negative regulation of protein localization to nucleolus
• GO:0042790 nucleolar large rRNA transcription by RNA polymerase I
• GO:0006363 termination of RNA polymerase I transcription
• GO:0006360 transcription by RNA polymerase I
• GO:0006362 transcription elongation by RNA polymerase I
• GO:0006361 transcription initiation at RNA polymerase I promoter

Disease associations

• acrofacial dysostosis Cincinnati type MONDO:0014651
• leukodystrophy, hypomyelinating, 27 MONDO:0958018

Drugs targeting this protein · 1

• TAS-106 inhibitor

Related proteins · sequence + function similarity

• DNA-directed RNA polymerase I subunit RPA1 0.99
• DNA-directed RNA polymerase I subunit RPA1 0.99
• DNA-directed RNA polymerase I subunit A 0.94
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit RPB1 0.91
• DNA-directed RNA polymerase II subunit rpb1 0.90
• DNA-directed RNA polymerase II subunit RPB1 0.90
• DNA-directed RNA polymerase II subunit RPB1 0.90

Co-cited proteins · studied together in the literature

• DNA-directed RNA polymerase I subunit RPA2 7 shared papers
• DNA-directed RNA polymerase I subunit RPA1 1 shared papers
• Oxysterol-binding protein-related protein 11 1 shared papers
• Nucleolar transcription factor 1 5 shared papers
• ATP-dependent DNA helicase Q5 1 shared papers
• ATP-dependent DNA helicase DDX11 1 shared papers
• DNA-directed RNA polymerase I subunit RPA34 4 shared papers
• DNA-directed RNA polymerase I subunit RPA49 4 shared papers
• TATA box-binding protein-associated factor RNA polymerase I subunit C 2 shared papers
• TATA box-binding protein-associated factor RNA polymerase I subunit A 2 shared papers
• TATA box-binding protein-associated factor RNA polymerase I subunit B 2 shared papers
• DNA-directed RNA polymerase I subunit RPA12 3 shared papers

Literature · 22 cited papers

• POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies. Am. J. Hum. Genet. · 2023
• A homozygous POLR1A variant causes leukodystrophy and affects protein homeostasis. Brain · 2023
• The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans. Life. Sci Alliance · 2022
• Cryo-EM structures of human RNA polymerase I. Nat. Struct. Mol. Biol. · 2021
• Structure of the human RNA polymerase I elongation complex. Cell Discov. · 2021
• Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A. Eur. J. Hum. Genet. · 2017
• RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells. J. Cell Biol. · 2016
• The Warsaw breakage syndrome-related protein DDX11 is required for ribosomal RNA synthesis and embryonic development. Hum. Mol. Genet. · 2015
• Acrofacial dysostosis, Cincinnati type, a mandibulofacial dysostosis syndrome with limb anomalies, is caused by POLR1A dysfunction. Am. J. Hum. Genet. · 2015
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. Cancer Res. · 2011
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• … and 10 more in the literature graph