POLR1A
Domain
The clamps form the DNA-binding cleft.
The bridging helix crosses the cleft near the catalytic site and is thought to promote polymerase translocation by acting as a ratchet that moves the DNA-RNA hybrid through the active site.
The trigger loop allows entry of NTPs into the active site, switching between an open and closed state with each NTP addition cycle.
The funnel accommodates POLR1H/RPA12 favoring mismatched RNA cleavage upon backtracking.
The high mobility group-like domain (dock II; residues 1060-1155) binds TOP2A, but cannot bind DNA; may assist Pol I initiation by releasing supercoils occurring during DNA unwinding.
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 (PubMed:11250903, PubMed:11283244, PubMed:16858408, PubMed:34671025, PubMed:34887565, PubMed:36271492). 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 (PubMed:11250903, PubMed:11283244, PubMed:16858408, PubMed:34671025, PubMed:34887565, PubMed:36271492). 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) (PubMed:11250903, PubMed:11283244, PubMed:16858408, PubMed:34671025, PubMed:34887565, PubMed:36271492).
Involvement in disease
Acrofacial dysostosis, Cincinnati type
AFDCIN
A form of acrofacial dysostosis, a group of disorders characterized by malformations of the craniofacial skeleton and, in some patients, the limbs. AFDCIN patients may also have structural cardiac defects and neurologic abnormalities including developmental delay, hypotonia, motor delay and seizures. AFDCIN inheritance is autosomal dominant.
None
The disease is caused by variants affecting the gene represented in this entry.
Leukodystrophy, hypomyelinating, 27
HLD27
A form of hypomyelinating leukodystrophy, a group of heterogeneous disorders characterized by persistent deficit of myelin observed on brain imaging. HLD27 is an autosomal recessive form characterized by global developmental delay apparent from infancy, poor or absent speech, ataxic gait or inability to sit or walk, spasticity, and abnormal eye movements. Some patients have seizures. Brain imaging shows hypomyelinating leukodystrophy, cerebellar atrophy, and thin corpus callosum.
None
The disease may be caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the RNA polymerase beta' chain family.
Cellular localization
- Nucleus
- Nucleolus
- Chromosome
Alternative names
DNA-directed RNA polymerase I subunit RPA1, RNA polymerase I subunit A1, A190, DNA-directed RNA polymerase I largest subunit, DNA-directed RNA polymerase I subunit A, RNA polymerase I 194 kDa subunit, RPA194, POLR1A