Biology:DNA polymerase alpha catalytic subunit
![]() Generic protein structure example |
DNA polymerase alpha catalytic subunit is an enzyme that in humans is encoded by the POLA1 gene.[1]
![](/wiki/images/thumb/3/37/Shared_primase-binding_peptide_in_archaeal_PolD_and_eukaryotic_Pol%CE%B1.pdf/page1-250px-Shared_primase-binding_peptide_in_archaeal_PolD_and_eukaryotic_Pol%CE%B1.pdf.jpg)
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
- ↑ "Entrez Gene: POLA1 polymerase (DNA directed), alpha 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5422.
- ↑ "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.
- ↑ "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.
- ↑ 4.0 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.
- ↑ "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.
- ↑ "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.
- ↑ "Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha". Oncogene 15 (20): 2483–2492. November 1997. doi:10.1038/sj.onc.1201431. PMID 9395244.
- ↑ "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.
- ↑ "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.
- ↑ "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
- "Regulation of eukaryotic DNA replication at the initiation step". Biochemical Society Transactions 31 (Pt 1): 266–269. February 2003. doi:10.1042/BST0310266. PMID 12546699.
- "DNA polymerase-alpha. Purification and structural characterization of the near homogeneous enzyme from human KB cells". The Journal of Biological Chemistry 252 (18): 6528–6535. September 1977. doi:10.1016/S0021-9258(17)39990-8. PMID 893425.
- "Interaction of DNA polymerase alpha-primase with cellular replication protein A and SV40 T antigen". The EMBO Journal 11 (2): 769–776. February 1992. doi:10.1002/j.1460-2075.1992.tb05110.x. PMID 1311258.
- "A role for the human single-stranded DNA binding protein HSSB/RPA in an early stage of nucleotide excision repair". Nucleic Acids Research 20 (15): 3873–3880. August 1992. doi:10.1093/nar/20.15.3873. PMID 1508673.
- "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. January 1992. doi:10.1016/0167-4781(92)90480-N. PMID 1730053.
- "Effects of T antigen and replication protein A on the initiation of DNA synthesis by DNA polymerase alpha-primase". Molecular and Cellular Biology 11 (4): 2108–2115. April 1991. doi:10.1128/mcb.11.4.2108. PMID 1848671.
- "On the association of DNA polymerase alpha activity with the nuclear matrix in HeLa cells". Cell Biology International Reports 15 (2): 131–140. February 1991. doi:10.1016/0309-1651(91)90104-Q. PMID 1903085.
- "Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells". Molecular and Cellular Biology 11 (4): 2081–2095. April 1991. doi:10.1128/mcb.11.4.2081. PMID 2005899.
- "Studies on the initiation and elongation reactions in the simian virus 40 DNA replication system". Proceedings of the National Academy of Sciences of the United States of America 87 (24): 9712–9716. December 1990. doi:10.1073/pnas.87.24.9712. PMID 2175912. Bibcode: 1990PNAS...87.9712M.
- "Human DNA polymerase alpha catalytic polypeptide binds ConA and RCA and contains a specific labile site in the N-terminus". Nucleic Acids Research 18 (21): 6231–6237. November 1990. doi:10.1093/nar/18.21.6231. PMID 2243771.
- "Assignment of the gene for human DNA polymerase alpha to the X chromosome". Proceedings of the National Academy of Sciences of the United States of America 82 (16): 5270–5274. August 1985. doi:10.1073/pnas.82.16.5270. PMID 2410918. Bibcode: 1985PNAS...82.5270W.
- "Protein-nucleic acid interaction in reactions catalyzed with DNA polymerases". Biochimie 70 (5): 655–661. May 1988. doi:10.1016/0300-9084(88)90250-7. PMID 3139084.
- "DNA repair synthesis in human fibroblasts requires DNA polymerase delta". The Journal of Biological Chemistry 263 (1): 501–510. January 1988. doi:10.1016/S0021-9258(19)57421-X. PMID 3335506.
- "Human DNA polymerase alpha gene expression is cell proliferation dependent and its primary structure is similar to both prokaryotic and eukaryotic replicative DNA polymerases". The EMBO Journal 7 (1): 37–47. January 1988. doi:10.1002/j.1460-2075.1988.tb02781.x. PMID 3359994.
- "Inhibition of human DNA polymerase alpha by alpha 1-antichymotrypsin". Cancer Research 46 (12 Pt 1): 6139–6142. December 1986. PMID 3490907.
- "Different populations of DNA polymerase alpha in HeLa cells". Journal of Molecular Biology 192 (1): 77–86. November 1986. doi:10.1016/0022-2836(86)90465-1. PMID 3820307.
- "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. December 1985. doi:10.1021/bi00346a061. PMID 4084590.
- "Intracellular localization of human DNA polymerase alpha with monoclonal antibodies". The Journal of Biological Chemistry 257 (14): 8391–8396. July 1982. doi:10.1016/S0021-9258(18)34344-8. PMID 7045121.
- "Preparation and preliminary characterization of monoclonal antibodies against human DNA polymerase alpha". The Journal of Biological Chemistry 257 (14): 8386–8390. July 1982. doi:10.1016/S0021-9258(18)34343-6. PMID 7085672.
- "Fidelity of DNA synthesis catalyzed by human DNA polymerase alpha and HIV-1 reverse transcriptase: effect of reaction pH". Nucleic Acids Research 21 (22): 5212–5220. November 1993. doi:10.1093/nar/21.22.5212. PMID 7504813.