This gene encodes the p180 catalytic subunit of DNA polymerase α-primase. Pol α has limitedprocessivity 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 ofOkazaki fragments on the lagging strand. The Pol α complex (pol α-DNA primase complex) consists of four subunits: the catalytic subunit POLA1, the regulatory subunitPOLA2, 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.
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 inX-linked reticulate pigmentary disorder (XLPDR), OMIM301220). 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 andhypogonadism.[10]
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^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.Bibcode:2000FEBSL.475..209N.doi:10.1016/S0014-5793(00)01679-3.PMID10869558.S2CID31594271.
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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.
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