DNA polymerase alpha catalytic subunit

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POLA1
Protein POLA1 PDB 1k0p.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPOLA1, NSX, POLA, p180, Polymerase (DNA directed), alpha 1, polymerase (DNA) alpha 1, catalytic subunit, DNA polymerase alpha 1, catalytic subunit, VEODS
External IDsOMIM: 312040 MGI: 99660 HomoloGene: 6802 GeneCards: POLA1
Gene location (Human)
X chromosome (human)
Chr.X chromosome (human)[1]
X chromosome (human)
Genomic location for POLA1
Genomic location for POLA1
BandXp22.11-p21.3Start24,693,909 bp[1]
End24,996,986 bp[1]
RNA expression pattern
PBB GE POLA1 204835 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_016937
NM_001330360

NM_008892

RefSeq (protein)

NP_001317289
NP_058633

NP_032918

Location (UCSC)Chr X: 24.69 – 25 MbChr X: 93.3 – 93.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

DNA polymerase alpha catalytic subunit is an enzyme that in humans is encoded by the POLA1 gene.[5]

Function[edit]

This gene encodes the p180 catalytic subunit of DNA polymerase α-primase. Pol α has limited processivity and lacks 3′ exonuclease activity for proofreading errors. Thus it is not well suited to efficiently and accurately copy long templates (unlike Pol Delta and Epsilon). Instead it plays a more limited role in replication. Pol α is responsible for the initiation of DNA replication at origins of replication (on both the leading and lagging strands) and during synthesis of Okazaki fragments on the lagging strand. The Pol α complex (pol α-DNA primase complex) consists of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the small and the large primase subunits PRIM1 and PRIM2 respectively. Once primase has created the RNA primer, Pol α starts replication elongating the primer with ~20 nucleotides.

Clinical significance[edit]

In addition to its role during DNA replication, POLA1 plays a role in type I interferon activation. The POLA1 gene was found to be the site of a mutation resulting in X-linked reticulate pigmentary disorder. This leads to altered mRNA splicing and decreased expression of POLA1 protein to a level that does not impair DNA replication. The reduction in POLA1 expression is accompanied by marked reduction in cytosolic RNA:DNA hybrid molecules and a concomitant hyperactivation of the IRF pathway, with consequent overproduction of type I interferons.[6]

Mutations in this gene has been associated with a syndrome of intellectual disability, proportionate short stature, microcephaly and hypogonadism.[7]

Interactions[edit]

DNA dependent polymerase alpha (Pol α) has been shown to interact with Retinoblastoma protein,[8] PARP1[9][10] and RBMS1.[11]

See also[edit]

External links[edit]

  • PDBe-KB provides an overview of all the structure information available in the PDB for Human DNA polymerase alpha catalytic subunit

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000101868 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006678 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: POLA1 polymerase (DNA directed), alpha 1".
  6. ^ Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, Pokatayev V, Dozmorov I, Khan S, Miyata N, Fraile G, Raj P, Xu Z, Xu Z, Ma L, Lin Z, Wang H, Yang Y, Ben-Amitai D, Orenstein N, Mussaffi H, Baselga E, Tadini G, Grunebaum E, Sarajlija A, Krzewski K, Wakeland EK, Yan N, de la Morena MT, Zinn AR, Burstein E (2016). "DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis". Nature Immunology. 17 (5): 495–504. doi:10.1038/ni.3409. PMC 4836962. PMID 27019227.
  7. ^ Van Esch H, Colnaghi R, Freson K, Starokadomskyy P, Zankl A, Backx L, Abramowicz I, Outwin E, Rohena L, Faulkner C, Leong GM, Newbury-Ecob RA, Challis RC, Õunap K, Jaeken J, Seuntjens E, Devriendt K, Burstein E, Low KJ, O'Driscoll M (April 2019). "Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism". American Journal of Human Genetics. 104: 957–967. doi:10.1016/j.ajhg.2019.03.006. PMC 6506757. PMID 31006512.
  8. ^ Takemura M, Kitagawa T, Izuta S, Wasa J, Takai A, Akiyama T, Yoshida S (November 1997). "Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha". Oncogene. 15 (20): 2483–92. doi:10.1038/sj.onc.1201431. PMID 9395244.
  9. ^ Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Ménissier-de Murcia J (April 1998). "Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication". Nucleic Acids Res. 26 (8): 1891–8. doi:10.1093/nar/26.8.1891. PMC 147507. PMID 9518481.
  10. ^ Simbulan CM, Suzuki M, Izuta S, Sakurai T, Savoysky E, Kojima K, Miyahara K, Shizuta Y, Yoshida S (Jan 1993). "Poly(ADP-ribose polymerase stimulates DNA polymerase alpha by physical association". J. Biol. Chem. 268 (1): 93–99. PMID 8416979.
  11. ^ Niki T, Galli I, Ariga H, Iguchi-Ariga SM (June 2000). "MSSP, a protein binding to an origin of replication in the c-myc gene, interacts with a catalytic subunit of DNA polymerase alpha and stimulates its polymerase activity". FEBS Lett. 475 (3): 209–12. doi:10.1016/S0014-5793(00)01679-3. PMID 10869558.