Biology:DNA polymerase alpha catalytic subunit

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

DNA polymerase alpha catalytic subunit is an enzyme that in humans is encoded by the POLA1 gene.[1]

Shared primase-binding peptide in archaeal PolD and eukaryotic Polα[2]

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.[3]

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.[4][5]

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.[6]

Interactions

DNA dependent polymerase alpha (Pol α) has been shown to interact with MCM4 and GINS1,[4] Retinoblastoma protein,[7] PARP1[8][9] and RBMS1.[10]

See also

  • DNA Polymerase
  • DNA polymerase alpha subunit 2

References

  1. ↑ "Entrez Gene: POLA1 polymerase (DNA directed), alpha 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5422. 
  2. ↑ "Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA". Nature Communications 11 (1): 1591. March 2020. doi:10.1038/s41467-020-15392-9. PMID 32221299. Bibcode: 2020NatCo..11.1591M. 
  3. ↑ "DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis". Nature Immunology 17 (5): 495–504. May 2016. doi:10.1038/ni.3409. PMID 27019227. 
  4. ↑ 4.0 4.1 "NK cell defects in X-linked pigmentary reticulate disorder". JCI Insight 4 (21). November 2019. doi:10.1172/jci.insight.125688. PMID 31672938. 
  5. ↑ "Evolution of the skin manifestations of X-linked pigmentary reticulate disorder". The British Journal of Dermatology 177 (5): e200–e201. November 2017. doi:10.1111/bjd.15586. PMID 28407217. 
  6. ↑ "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. May 2019. doi:10.1016/j.ajhg.2019.03.006. PMID 31006512. 
  7. ↑ "Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha". Oncogene 15 (20): 2483–2492. November 1997. doi:10.1038/sj.onc.1201431. PMID 9395244. 
  8. ↑ "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. April 1998. doi:10.1093/nar/26.8.1891. PMID 9518481. 
  9. ↑ "Poly(ADP-ribose) polymerase stimulates DNA polymerase alpha by physical association". The Journal of Biological Chemistry 268 (1): 93–99. January 1993. doi:10.1016/S0021-9258(18)54119-3. PMID 8416979. 
  10. ↑ "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. June 2000. doi:10.1016/S0014-5793(00)01679-3. PMID 10869558. 

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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