 | This articleneeds additional citations forverification. Please helpimprove this article byadding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "PrimPol" – news ·newspapers ·books ·scholar ·JSTOR(October 2014) (Learn how and when to remove this message) |
PrimPol is aprotein encoded by thePRIMPOL gene in humans.[5][6][7] PrimPol is a eukaryotic protein with bothDNA polymerase andDNA Primase activities involved intranslesion DNA synthesis. It is the first eukaryotic protein to be identified with priming activity usingdeoxyribonucleotides.[6][7] It is also the first protein identified in themitochondria to have translesion DNA synthesis activities.
PrimPol was identified in a bioinformatic study and initially presumed to only haveprimase activity.[8] Subsequentin vitro andin vivo studies have shown it to have both primase andpolymerase activities that both localise to the catalytic domain of PrimPol.[6][7][9] For that reason, this protein was assigned the name PrimPol.
PrimPol is a DNA primase and DNA polymerase involved inDNA 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.[6][7] PrimPol preferentially initiates replication usingdeoxynucleotides, rather thanribonucleotides 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 increasedRPA foci.[6][7]
PrimPol is predicted to play a role in translesion DNA synthesis. When thereplication 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 tochromatin following UV irradiation.[6] PrimPol is able to bypass the highly distortivePyrimidine dimers produced as a result of UV irradiation of DNAin vitro.[6][7] PrimPol requires its primase activity to bypass UV lesionsin vivo without stalling.[9][10] 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 the8-Oxoguanine bases that are produced in response to oxidative stress, this is of particular importance in the oxidative environment of themitochondria.[7] The replicative DNA polymerase identified in the mitochondria,pol γ, deals with these lesions poorly. Furthermore, PrimPol is capable of bypassing anAP site in approximately 80% of cases.[7]
PrimPol is formed of twoprotein domains, a catalytic primase-polymerase domain and a zinc finger domain.[6][7] The primase and polymerase catalytic functions of PrimPol localise to the primase-polymerase domain but primase activity of PrimPol requires the zinc finger domain.[9][10]
PrimPol has been found to be mainly located in thecytosol (47%), with large fractions also found in the mitochondria (34%), and nuclear compartments (19%).[7] 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.
A mutation in thePRIMPOL gene has been correlated withmyopia.[11][12] 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 forksin vivo.[12]
