DNA polymerase alpha catalytic subunit is an enzyme that in humans is encoded by the POLA1gene.[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]
^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. PMID9395244.
^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. PMID10869558. S2CID31594271.
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
Pollok S, Stoepel J, Bauerschmidt C, Kremmer E, Nasheuer HP (February 2003). "Regulation of eukaryotic DNA replication at the initiation step". Biochemical Society Transactions. 31 (Pt 1): 266–269. doi:10.1042/BST0310266. PMID12546699.
Popanda O, Thielmann HW (January 1992). "The function of DNA polymerases in DNA repair synthesis of ultraviolet-irradiated human fibroblasts". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1129 (2): 155–160. doi:10.1016/0167-4781(92)90480-N. PMID1730053.
Martelli AM, Cocco L, Manzoli FA (February 1991). "On the association of DNA polymerase alpha activity with the nuclear matrix in HeLa cells". Cell Biology International Reports. 15 (2): 131–140. doi:10.1016/0309-1651(91)90104-Q. PMID1903085.
Tsuda M, Masuyama M, Katsunuma T (December 1986). "Inhibition of human DNA polymerase alpha by alpha 1-antichymotrypsin". Cancer Research. 46 (12 Pt 1): 6139–6142. PMID3490907.
Jackson DA, Cook PR (November 1986). "Different populations of DNA polymerase alpha in HeLa cells". Journal of Molecular Biology. 192 (1): 77–86. doi:10.1016/0022-2836(86)90465-1. PMID3820307.
Miller MR, Seighman C, Ulrich RG (December 1985). "Inhibition of DNA replication and DNA polymerase alpha activity by monoclonal anti-(DNA polymerase alpha) immunoglobulin G and F(ab) fragments". Biochemistry. 24 (25): 7440–7445. doi:10.1021/bi00346a061. PMID4084590.
