View source for DNA polymerase alpha catalytic subunit

{{Short description|Class of enzymes}}
{{redirect|POLA1|the gene|POLA1 (gene)}}
{{Infobox_gene}}
'''DNA polymerase alpha catalytic subunit''' is an [[enzyme]] that in humans is encoded by the ''POLA1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: POLA1 polymerase (DNA directed), alpha 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5422}}</ref>
[[File:Shared primase-binding peptide in archaeal PolD and eukaryotic Polα.pdf|thumb|Shared primase-binding peptide in archaeal [[DNA polymerase#Family D|PolD]] and eukaryotic Polα<ref>{{cite journal | vauthors = Madru C, Henneke G, Raia P, Hugonneau-Beaufet I, Pehau-Arnaudet G, England P, Lindahl E, Delarue M, Carroni M, Sauguet L | display-authors = 6 | title = Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA | journal = Nature Communications | volume = 11 | issue = 1 | pages = 1591 | date = March 2020 | pmid = 32221299 | doi = 10.1038/s41467-020-15392-9 | pmc = 7101311 | bibcode = 2020NatCo..11.1591M }}</ref>]]
== 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 fragment]]s 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|X-linked reticulate pigmentary disorder (XLPDR)]], OMIM [https://www.omim.org/entry/301220 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.<ref name="pmid27019227">{{cite journal | vauthors = Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, Pokatayev V, Dozmorov I, Khan S, Miyata N, Fraile G, Raj P, Xu Z, Xu Z, Ma L, Lin Z, Wang H, Yang Y, Ben-Amitai D, Orenstein N, Mussaffi H, Baselga E, Tadini G, Grunebaum E, Sarajlija A, Krzewski K, Wakeland EK, Yan N, de la Morena MT, Zinn AR, Burstein E | display-authors = 6 | title = DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis | journal = Nature Immunology | volume = 17 | issue = 5 | pages = 495–504 | date = May 2016 | pmid = 27019227 | pmc = 4836962 | doi = 10.1038/ni.3409 }}</ref>
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.<ref name=":0">{{cite journal | vauthors = Starokadomskyy P, Wilton KM, Krzewski K, Lopez A, Sifuentes-Dominguez L, Overlee B, Chen Q, Ray A, Gil-Krzewska A, Peterson M, Kinch LN, Rohena L, Grunebaum E, Zinn AR, Grishin NV, Billadeau DD, Burstein E | display-authors = 6 | title = NK cell defects in X-linked pigmentary reticulate disorder | journal = JCI Insight | volume = 4 | issue = 21 | date = November 2019 | pmid = 31672938 | pmc = 6948767 | doi = 10.1172/jci.insight.125688 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Starokadomskyy P, Sifuentes-Dominguez L, Gemelli T, Zinn AR, Dossi MT, Mellado C, Bertrand P, Borzutzky A, Burstein E | display-authors = 6 | title = Evolution of the skin manifestations of X-linked pigmentary reticulate disorder | journal = The British Journal of Dermatology | volume = 177 | issue = 5 | pages = e200–e201 | date = November 2017 | pmid = 28407217 | pmc = 5640471 | doi = 10.1111/bjd.15586 }}</ref>
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]].<ref name="pmid31006512">{{cite journal | vauthors = Van Esch H, Colnaghi R, Freson K, Starokadomskyy P, Zankl A, Backx L, Abramowicz I, Outwin E, Rohena L, Faulkner C, Leong GM, Newbury-Ecob RA, Challis RC, Õunap K, Jaeken J, Seuntjens E, Devriendt K, Burstein E, Low KJ, O'Driscoll M | display-authors = 6 | title = Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism | journal = American Journal of Human Genetics | volume = 104 | issue = 5 | pages = 957–967 | date = May 2019 | pmid = 31006512 | pmc = 6506757 | doi = 10.1016/j.ajhg.2019.03.006 }}</ref>
== Interactions ==
DNA dependent polymerase alpha (Pol α) has been shown to [[Protein-protein interaction|interact]] with [[MCM4]] and [[GINS1]],<ref name=":0" /> [[Retinoblastoma protein]],<ref name=pmid9395244>{{cite journal | vauthors = Takemura M, Kitagawa T, Izuta S, Wasa J, Takai A, Akiyama T, Yoshida S | title = Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha | journal = Oncogene | volume = 15 | issue = 20 | pages = 2483–2492 | date = November 1997 | pmid = 9395244 | doi = 10.1038/sj.onc.1201431 | doi-access =  }}</ref> [[PARP1]]<ref name=pmid9518481>{{cite journal | vauthors = Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Ménissier-de Murcia J | title = Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication | journal = Nucleic Acids Research | volume = 26 | issue = 8 | pages = 1891–1898 | date = April 1998 | pmid = 9518481 | pmc = 147507 | doi = 10.1093/nar/26.8.1891 }}</ref><ref>{{cite journal | vauthors = Simbulan CM, Suzuki M, Izuta S, Sakurai T, Savoysky E, Kojima K, Miyahara K, Shizuta Y, Yoshida S | display-authors = 6 | title = Poly(ADP-ribose) polymerase stimulates DNA polymerase alpha by physical association | journal = The Journal of Biological Chemistry | volume = 268 | issue = 1 | pages = 93–99 | date = January 1993 | pmid = 8416979 | doi = 10.1016/S0021-9258(18)54119-3 | doi-access = free }}</ref> and [[RBMS1]].<ref name=pmid10869558>{{cite journal | vauthors = Niki T, Galli I, Ariga H, Iguchi-Ariga SM | title = 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 | journal = FEBS Letters | volume = 475 | issue = 3 | pages = 209–212 | date = June 2000 | pmid = 10869558 | doi = 10.1016/S0014-5793(00)01679-3 | s2cid = 31594271 }}</ref>
== See also ==
* [[DNA Polymerase]]
* [[DNA polymerase alpha subunit 2]]
== References ==
{{reflist}}
{{Clear}}
== External links ==
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P09884 PDBe-KB] provides an overview of all the structure information available in the PDB for Human DNA polymerase alpha catalytic subunit
== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Pollok S, Stoepel J, Bauerschmidt C, Kremmer E, Nasheuer HP | title = Regulation of eukaryotic DNA replication at the initiation step | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 1 | pages = 266–269 | date = February 2003 | pmid = 12546699 | doi = 10.1042/BST0310266 | doi-access =  }}
* {{cite journal | vauthors = Fisher PA, Korn D | title = DNA polymerase-alpha. Purification and structural characterization of the near homogeneous enzyme from human KB cells | journal = The Journal of Biological Chemistry | volume = 252 | issue = 18 | pages = 6528–6535 | date = September 1977 | pmid = 893425 | doi = 10.1016/S0021-9258(17)39990-8 | doi-access = free }}
* {{cite journal | vauthors = Dornreiter I, Erdile LF, Gilbert IU, von Winkler D, Kelly TJ, Fanning E | title = Interaction of DNA polymerase alpha-primase with cellular replication protein A and SV40 T antigen | journal = The EMBO Journal | volume = 11 | issue = 2 | pages = 769–776 | date = February 1992 | pmid = 1311258 | pmc = 556510 | doi = 10.1002/j.1460-2075.1992.tb05110.x }}
* {{cite journal | vauthors = Coverley D, Kenny MK, Lane DP, Wood RD | title = A role for the human single-stranded DNA binding protein HSSB/RPA in an early stage of nucleotide excision repair | journal = Nucleic Acids Research | volume = 20 | issue = 15 | pages = 3873–3880 | date = August 1992 | pmid = 1508673 | pmc = 334061 | doi = 10.1093/nar/20.15.3873 }}
* {{cite journal | vauthors = Popanda O, Thielmann HW | title = The function of DNA polymerases in DNA repair synthesis of ultraviolet-irradiated human fibroblasts | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1129 | issue = 2 | pages = 155–160 | date = January 1992 | pmid = 1730053 | doi = 10.1016/0167-4781(92)90480-N }}
* {{cite journal | vauthors = Collins KL, Kelly TJ | title = Effects of T antigen and replication protein A on the initiation of DNA synthesis by DNA polymerase alpha-primase | journal = Molecular and Cellular Biology | volume = 11 | issue = 4 | pages = 2108–2115 | date = April 1991 | pmid = 1848671 | pmc = 359898 | doi = 10.1128/mcb.11.4.2108 }}
* {{cite journal | vauthors = Martelli AM, Cocco L, Manzoli FA | title = On the association of DNA polymerase alpha activity with the nuclear matrix in HeLa cells | journal = Cell Biology International Reports | volume = 15 | issue = 2 | pages = 131–140 | date = February 1991 | pmid = 1903085 | doi = 10.1016/0309-1651(91)90104-Q }}
* {{cite journal | vauthors = Pearson BE, Nasheuer HP, Wang TS | title = Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells | journal = Molecular and Cellular Biology | volume = 11 | issue = 4 | pages = 2081–2095 | date = April 1991 | pmid = 2005899 | pmc = 359896 | doi = 10.1128/mcb.11.4.2081 }}
* {{cite journal | vauthors = Matsumoto T, Eki T, Hurwitz J | title = Studies on the initiation and elongation reactions in the simian virus 40 DNA replication system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 24 | pages = 9712–9716 | date = December 1990 | pmid = 2175912 | pmc = 55243 | doi = 10.1073/pnas.87.24.9712 | bibcode = 1990PNAS...87.9712M | doi-access = free }}
* {{cite journal | vauthors = Hsi KL, Copeland WC, Wang TS | title = Human DNA polymerase alpha catalytic polypeptide binds ConA and RCA and contains a specific labile site in the N-terminus | journal = Nucleic Acids Research | volume = 18 | issue = 21 | pages = 6231–6237 | date = November 1990 | pmid = 2243771 | pmc = 332486 | doi = 10.1093/nar/18.21.6231 }}
* {{cite journal | vauthors = Wang TS, Pearson BE, Suomalainen HA, Mohandas T, Shapiro LJ, Schröder J, Korn D | title = Assignment of the gene for human DNA polymerase alpha to the X chromosome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 16 | pages = 5270–5274 | date = August 1985 | pmid = 2410918 | pmc = 390549 | doi = 10.1073/pnas.82.16.5270 | doi-access = free | bibcode = 1985PNAS...82.5270W }}
* {{cite journal | vauthors = Knorre DG, Lavrik OI, Nevinsky GA | title = Protein-nucleic acid interaction in reactions catalyzed with DNA polymerases | journal = Biochimie | volume = 70 | issue = 5 | pages = 655–661 | date = May 1988 | pmid = 3139084 | doi = 10.1016/0300-9084(88)90250-7 }}
* {{cite journal | vauthors = Nishida C, Reinhard P, Linn S | title = DNA repair synthesis in human fibroblasts requires DNA polymerase delta | journal = The Journal of Biological Chemistry | volume = 263 | issue = 1 | pages = 501–510 | date = January 1988 | pmid = 3335506 | doi = 10.1016/S0021-9258(19)57421-X | doi-access = free }}
* {{cite journal | vauthors = Wong SW, Wahl AF, Yuan PM, Arai N, Pearson BE, Arai K, Korn D, Hunkapiller MW, Wang TS | display-authors = 6 | title = Human DNA polymerase alpha gene expression is cell proliferation dependent and its primary structure is similar to both prokaryotic and eukaryotic replicative DNA polymerases | journal = The EMBO Journal | volume = 7 | issue = 1 | pages = 37–47 | date = January 1988 | pmid = 3359994 | pmc = 454213 | doi = 10.1002/j.1460-2075.1988.tb02781.x }}
* {{cite journal | vauthors = Tsuda M, Masuyama M, Katsunuma T | title = Inhibition of human DNA polymerase alpha by alpha 1-antichymotrypsin | journal = Cancer Research | volume = 46 | issue = 12 Pt 1 | pages = 6139–6142 | date = December 1986 | pmid = 3490907 }}
* {{cite journal | vauthors = Jackson DA, Cook PR | title = Different populations of DNA polymerase alpha in HeLa cells | journal = Journal of Molecular Biology | volume = 192 | issue = 1 | pages = 77–86 | date = November 1986 | pmid = 3820307 | doi = 10.1016/0022-2836(86)90465-1 }}
* {{cite journal | vauthors = Miller MR, Seighman C, Ulrich RG | title = Inhibition of DNA replication and DNA polymerase alpha activity by monoclonal anti-(DNA polymerase alpha) immunoglobulin G and F(ab) fragments | journal = Biochemistry | volume = 24 | issue = 25 | pages = 7440–7445 | date = December 1985 | pmid = 4084590 | doi = 10.1021/bi00346a061 }}
* {{cite journal | vauthors = Bensch KG, Tanaka S, Hu SZ, Wang TS, Korn D | title = Intracellular localization of human DNA polymerase alpha with monoclonal antibodies | journal = The Journal of Biological Chemistry | volume = 257 | issue = 14 | pages = 8391–8396 | date = July 1982 | pmid = 7045121 | doi = 10.1016/S0021-9258(18)34344-8 | doi-access = free }}
* {{cite journal | vauthors = Tanaka S, Hu SZ, Wang TS, Korn D | title = Preparation and preliminary characterization of monoclonal antibodies against human DNA polymerase alpha | journal = The Journal of Biological Chemistry | volume = 257 | issue = 14 | pages = 8386–8390 | date = July 1982 | pmid = 7085672 | doi = 10.1016/S0021-9258(18)34343-6 | doi-access = free }}
* {{cite journal | vauthors = Eckert KA, Kunkel TA | title = Fidelity of DNA synthesis catalyzed by human DNA polymerase alpha and HIV-1 reverse transcriptase: effect of reaction pH | journal = Nucleic Acids Research | volume = 21 | issue = 22 | pages = 5212–5220 | date = November 1993 | pmid = 7504813 | pmc = 310639 | doi = 10.1093/nar/21.22.5212 }}
{{refend}}
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