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PrimPol is a protein encoded by the PRIMPOL gene in humans. PrimPol is a eukaryotic protein with both DNA polymerase and DNA Primase activities involved in translesion DNA synthesis. It is the first eukaryotic protein to be identified with priming activity using deoxyribonucleotides. It is also the first protein identified in the mitochondria to have translesion DNA synthesis activities.
Etymology
PrimPol was identified in a bioinformatic study and initially presumed to only have primase activity. Subsequent in vitro and in vivo studies have shown it to have both primase and polymerase activities that both localise to the catalytic domain of PrimPol. For that reason, this protein was assigned the name PrimPol.
Function
PrimPol is a DNA primase and DNA polymerase involved in DNA replication. Unlike the other known DNA polymerases, PrimPol can initiate replication without the need of an RNA primer and can extend from primers produced by PrimPol. PrimPol preferentially initiates replication using deoxynucleotides, rather than ribonucleotides and will only extend from a nascent DNA chain using deoxynucleotides. PrimPol exhibits a 1000-fold bias towards Watson-Crick base pairing when extending DNA chains. PrimPol plays an as yet unidentified role in unperturbed replication, PrimPol depleted cells slow replication fork progression, proliferate slower and show an increased RPA foci.
Translesion DNA synthesis
PrimPol is predicted to play a role in translesion DNA synthesis. When the replication fork reaches a site of DNA damage it stalls, which can lead to lethal single stranded gaps and double strand breaks. PrimPol is one of a number of polymerases that can be recruited to replicate past sites of DNA damage. PrimPol localises to chromatin following UV irradiation. PrimPol is able to bypass the highly distortive Pyrimidine dimers produced as a result of UV irradiation of DNA in vitro. PrimPol requires its primase activity to bypass UV lesions in vivo without stalling. Taken together these data suggest that PrimPol has two separate modes of action to bypass lesions, one in direct read-through of lesions in a classical translesion DNA synthesis manner and one in priming downstream of the lesion and the gap filled in postreplicatively.
In addition to UV lesions, PrimPol is capable of bypassing the 8-Oxoguanine bases that are produced in response to oxidative stress, this is of particular importance in the oxidative environment of the mitochondria. The replicative DNA polymerase identified in the mitochondria, pol γ, deals with these lesions poorly. Furthermore, PrimPol is capable of bypassing an AP site in approximately 80% of cases.
Structure
PrimPol is formed of two protein domains, a catalytic primase-polymerase domain and a zinc finger domain. The primase and polymerase catalytic functions of PrimPol localise to the primase-polymerase domain but primase activity of PrimPol requires the zinc finger domain.
Subcellular localization
PrimPol has been found to be mainly located in the cytosol (47%), with large fractions also found in the mitochondria (34%), and nuclear compartments (19%). The mitochondrial fraction of PrimPol is found to be in the matrix of the mitochondria, as opposed to the either the membrane or intermembrane space.
PrimPol mutations
A mutation in the PRIMPOL gene has been correlated with myopia. This tyrosine to aspartate (Y89D) mutation has been shown to produce a poorly processive variant of the PrimPol protein, and this Y89D variant impedes replication forks in vivo.
References
- ^ GRCh38: Ensembl release 89: ENSG00000164306 – Ensembl, May 2017
- ^ GRCm38: Ensembl release 89: ENSMUSG00000038225 – Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Entrez Gene: Entrez Gene: PRIMPOL primase and polymerase (DNA-directed)".
- ^ Bianchi J, Rudd SJ, Jozwiakowski SK, Bailey LJ, Soura V, Taylor E, Stevanovic I, Green AJ, Stracker TH, Lindsay HD, Doherty AJ (Nov 2014). "PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication". Molecular Cell. 52 (4): 566–73. doi:10.1016/j.molcel.2013.10.035. PMC 4228047. PMID 24267451.
- ^ García-Gómez S, Reyes A, Martínez-Jiménez MI, Chocrón ES, Mourón S, Terrados G, Powell C, Salido E, Méndez J, Holt IJ, Blanco L (Nov 2014). "PrimPol, an archaic primase/polymerase operating in human cells". Molecular Cell. 52 (4): 541–53. doi:10.1016/j.molcel.2013.09.025. PMC 3899013. PMID 24207056.
- Iyer LM, Koonin EV, Leipe DD, Aravind L (Jul 2005). "Origin and evolution of the archaeo-eukaryotic primase superfamily and related palm-domain proteins: structural insights and new members". Nucleic Acids Research. 33 (12): 3875–96. doi:10.1093/nar/gki702. PMC 1176014. PMID 16027112.
- ^ Keen BA, Jozwiakowski SK, Bailey LJ, Bianchi J, Doherty AJ (Mar 2014). "Molecular dissection of the domain architecture and catalytic activities of human PrimPol". Nucleic Acids Research. 42 (9): 5830–45. doi:10.1093/nar/gku214. PMC 4027207. PMID 24682820.
- ^ Mourón S, Rodriguez-Acebes S, Martínez-Jiménez MI, García-Gómez S, Chocrón S, Blanco L, Méndez J (Nov 2013). "Repriming of DNA synthesis at stalled replication forks by human PrimPol". Nature Structural & Molecular Biology. 20 (12): 1383–9. doi:10.1038/nsmb.2719. hdl:10261/98409. PMID 24240614. S2CID 28904104.
- Zhao F, Wu J, Xue A, Su Y, Wang X, Lu X, Zhou Z, Qu J, Zhou X (Apr 2013). "Exome sequencing reveals CCDC111 mutation associated with high myopia". Human Genetics. 132 (8): 913–21. doi:10.1007/s00439-013-1303-6. PMID 23579484. S2CID 16845466.
- ^ Keen BA, Bailey LJ, Jozwiakowski SK, Doherty AJ (Sep 2014). "Human PrimPol mutation associated with high myopia has a DNA replication defect". Nucleic Acids Research. 42 (19): 12102–11. doi:10.1093/nar/gku879. PMC 4231748. PMID 25262353.