DNA polymerase alpha catalytic subunit

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"POLA1" redirects here. For the gene, see POLA1 (gene).
POLA1
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
Orthologs
SpeciesHumanMouse
Entrez

5422

18968

Ensembl

ENSG00000101868

ENSMUSG00000006678

UniProt

P09884

P33609

RefSeq (mRNA)

NM_016937
NM_001330360
NM_001378303

NM_008892

RefSeq (protein)

NP_001317289
NP_058633
NP_001365232

NP_032918

Location (UCSC)Chr X: 24.69 – 25 MbChr X: 92.35 – 92.68 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]

Shared primase-binding peptide in archaeal PolD and eukaryotic Polα[6]

Function

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

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 (XLPDR), OMIM 301220). 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 IRF3 pathway, with consequent overproduction of type I interferons.[7]

Moreover, POLA1 deficiency, typical for XLPDR, also impair direct cytotoxicity of NK cells. POLA1 inhibition or a natural deficiency (XLPDR) affects the way the lytic granules secreted toward target cells. As a result, NK cells in XLPDR patients display functional deficiency. Interestingly, the POLA1 deficiency typical for XLPDR is not associated with any genomic damages or cell cycle arrest.[8][9]

While the XLPDR mutation is resided in intron 13th, other somatic mutations in POLA1 were also described. Somatic mutation are associated with more profound deficiency of POLA1, with develops into X-linked intellectual disability (XLID). In a case of non-XLPDR mutations, beside of type I interferon signature patients also display mild to medium signs of intellectual disability, cell cycle arrest, proportionate short stature, microcephaly and hypogonadism.[10]

Interactions

DNA dependent polymerase alpha (Pol α) has been shown to interact with MCM4 and GINS1,[8] Retinoblastoma protein,[11] PARP1[12][13] and RBMS1.[14]

See also

References

  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. ^ Madru C, Henneke G, Raia P, Hugonneau-Beaufet I, Pehau-Arnaudet G, England P, et al. (March 2020). "Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA". Nature Communications. 11 (1): 1591. Bibcode:2020NatCo..11.1591M. doi:10.1038/s41467-020-15392-9. PMC 7101311. PMID 32221299.
  7. ^ Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, et al. (May 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.
  8. ^ a b Starokadomskyy P, Wilton KM, Krzewski K, Lopez A, Sifuentes-Dominguez L, Overlee B, et al. (November 2019). "NK cell defects in X-linked pigmentary reticulate disorder". JCI Insight. 4 (21). doi:10.1172/jci.insight.125688. PMC 6948767. PMID 31672938.
  9. ^ Starokadomskyy P, Sifuentes-Dominguez L, Gemelli T, Zinn AR, Dossi MT, Mellado C, et al. (November 2017). "Evolution of the skin manifestations of X-linked pigmentary reticulate disorder". The British Journal of Dermatology. 177 (5): e200–e201. doi:10.1111/bjd.15586. PMC 5640471. PMID 28407217.
  10. ^ Van Esch H, Colnaghi R, Freson K, Starokadomskyy P, Zankl A, Backx L, et al. (May 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 (5): 957–967. doi:10.1016/j.ajhg.2019.03.006. PMC 6506757. PMID 31006512.
  11. ^ 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): 2483–2492. doi:10.1038/sj.onc.1201431. PMID 9395244.
  12. ^ 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 Research. 26 (8): 1891–1898. doi:10.1093/nar/26.8.1891. PMC 147507. PMID 9518481.
  13. ^ Simbulan CM, Suzuki M, Izuta S, Sakurai T, Savoysky E, Kojima K, et al. (January 1993). "Poly(ADP-ribose) polymerase stimulates DNA polymerase alpha by physical association". The Journal of Biological Chemistry. 268 (1): 93–99. doi:10.1016/S0021-9258(18)54119-3. PMID 8416979.
  14. ^ 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 Letters. 475 (3): 209–212. doi:10.1016/S0014-5793(00)01679-3. PMID 10869558. S2CID 31594271.

External links

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

Further reading

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