DNA polymerase alpha catalytic subunit
Also known as: POLA, POLA1
Function
Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, a regulatory subunit POLA2 and two primase subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses.
Classification
- Family (Pfam)
- PF12254 DNA_pol_alpha_N, PF00136 DNA_pol_B, PF03104 DNA_pol_B_exo1, PF08996 zf-DNA_Pol
- InterPro
- DNA-dir_DNA_pol_B, DNA-dir_DNA_pol_B_CS, DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA/RNA_pol_sf, DNA_pol_a_cat_su_N, DNA_pol_B_thumb, DNA_pol_palm_dom_sf, Pol_alpha_znc_sf, POLBc_alpha, RNaseH-like_sf, RNaseH_sf, Znf_DNA-dir_DNA_pol_B_alpha
- Functional cluster
- DEAD-Box RNA Helicases & Biogenesis Factors
Experimental structures · PDB · 21
- 1K0P NMR
- 1K18 NMR
- 1N5G NMR
- 4Q5V X-ray 2.52A
- 4QCL X-ray 2.20A
- 4Y97 X-ray 2.51A
- 5EXR X-ray 3.60A
- 5IUD X-ray 3.30A
- 6AS7 X-ray 2.95A
- 7N2M X-ray 2.90A
- 7OPL EM 4.12A
- 7U5C EM 4.60A
- … and 9 more
A predicted model is available from AlphaFold.
Gene Ontology · 27
- GO:0005658 alpha DNA polymerase:primase complex
- GO:0000785 chromatin
- GO:0005829 cytosol
- GO:0005635 nuclear envelope
- GO:0016363 nuclear matrix
- GO:0005730 nucleolus
- GO:0005654 nucleoplasm
- GO:0005634 nucleus
- GO:0003682 chromatin binding
- GO:0003677 DNA binding
- GO:0003688 DNA replication origin binding
- GO:0003887 DNA-directed DNA polymerase activity
- GO:0000166 nucleotide binding
- GO:0019901 protein kinase binding
- GO:0003697 single-stranded DNA binding
- GO:0008270 zinc ion binding
- GO:0006281 DNA repair
- GO:0006260 DNA replication
- GO:0006270 DNA replication initiation
- GO:0006269 DNA replication, synthesis of primer
- GO:0006271 DNA strand elongation involved in DNA replication
- GO:0000731 DNA synthesis involved in DNA repair
- GO:0006303 double-strand break repair via nonhomologous end joining
- GO:0006273 lagging strand elongation
- GO:0006272 leading strand elongation
- GO:1902975 mitotic DNA replication initiation
- GO:0032479 regulation of type I interferon production
Disease associations
- X-linked intellectual disability, van Esch type MONDO:0015601
- X-linked reticulate pigmentary disorder MONDO:0010523
Drugs targeting this protein · 6
- FLUDARABINE PHOSPHATE inhibitor
- GEMCITABINE HYDROCHLORIDE inhibitor
- CLOFARABINE inhibitor
- TROXACITABINE inhibitor
- ASPACYTARABINE inhibitor
- CYTARABINE inhibitor
Related proteins · sequence + function similarity
- DNA polymerase alpha catalytic subunit 0.98
- DNA polymerase alpha catalytic subunit 0.97
- DNA polymerase alpha catalytic subunit 0.95
- DNA polymerase alpha catalytic subunit 0.85
- DNA polymerase alpha catalytic subunit 0.81
- DNA polymerase alpha catalytic subunit A 0.79
- DNA polymerase alpha catalytic subunit 0.79
- DNA polymerase alpha catalytic subunit 0.79
- DNA polymerase alpha catalytic subunit 0.79
- DNA polymerase catalytic subunit 0.71
- DNA polymerase catalytic subunit 0.71
- DNA polymerase alpha catalytic subunit 0.70
Co-cited proteins · studied together in the literature
- DNA polymerase alpha catalytic subunit 1 shared papers
- DNA polymerase alpha subunit B 2 shared papers
- Protein MCM10 homolog 1 shared papers
- DNA primase small subunit 2 shared papers
- DNA primase large subunit 2 shared papers
- Large T antigen 1 shared papers
- Replication protein A 70 kDa DNA-binding subunit 1 shared papers
- Poly [ADP-ribose] polymerase 1 1 shared papers
Literature · 20 cited papers
- Defective DNA Polymerase alpha-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism. Am. J. Hum. Genet. · 2019
- DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat. Immunol. · 2016
- Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome. J. Biol. Chem. · 2016
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci. Signal. · 2011
- Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
- Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. · 2010
- Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
- Physical interactions between Mcm10, DNA, and DNA polymerase alpha. J. Biol. Chem. · 2009
- A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
- Nuclear magnetic resonance structures of the zinc finger domain of human DNA polymerase-alpha. Biochim. Biophys. Acta · 2003
- Primase activity of human DNA polymerase alpha-primase. Divalent cations stabilize the enzyme activity of the p48 subunit. J. Biol. Chem. · 1998
- … and 8 more in the literature graph