PrimPol-A new polymerase on the block - PubMed (original) (raw)

Review

PrimPol-A new polymerase on the block

Sean G Rudd et al. Mol Cell Oncol. 2014.

Abstract

The DNA-directed primase-polymerase PrimPol of the archaeo-eukaryotic primase superfamily represents an ancient solution to the many problems faced during genome duplication. This versatile enzyme is capable of initiating de novo DNA/RNA synthesis, DNA chain elongation, and has the capacity to bypass modifications that stall the replisome by trans-lesion synthesis or origin-independent re-priming, thus allowing discontinuous synthesis of the leading strand. Recent studies have shown that PrimPol is an important new player in replication fork progression in eukaryotic cells; this review summarizes our current understanding of PrimPol and highlights important questions that remain to be addressed.

Keywords: AEP; DNA; PrimPol; TLS; lesions; polymerase; primase; replication; repriming; restart.

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Figures

Figure 1.

Figure 1.

The domain organization of members of the archaeo-eukaryotic primase superfamily. Domain organization of various AEPs is depicted: motifs I, II, and III of the catalytic AEP domain (blue boxes), zinc finger (Zn) motifs (red boxes), and additional domains often associated with AEP enzymes are shown. The putative or characterized role of each AEP is indicated. Domain organizations were deduced from the article by Iyer et al.

Figure 2.

Figure 2.

Conserved domains and motifs present in the PrimPol family. The catalytic archaeo-eukaryotic primase (AEP) domain containing 3 signature motifs (I, II, and III; blue boxes), the UL52-like zinc finger domain (Zn), and the replication protein A (RPA)-interaction site (orange box) are indicated for human PrimPol, including amino acid numbers. Multiple sequence alignment was generated for a selection of PrimPol homologues; blue shading indicates ≥40% sequence identity, red circles indicate residues required for metal ion binding, orange circles indicate those required for nucleotide binding, and green circles those required for chelation of zinc.

Figure 3.

Figure 3.

PrimPol is a versatile DNA/RNA primase-polymerase in vitro. The reported in vitro activities of human PrimPol are represented schematically. Some activities are dependent on specific metal co-factors: for example, template scrunching to facilitate bypass and template-independent terminal transferase activity are only observed when manganese ions are used as co-factors. TLS, translesion synthesis; 8-oxo-guanine, 8-oxo-G; pyrimidine (6-4) pyrimidone photoproduct, 6-4 PP; apurinic/apyrimidinic site, AP site; cyclobutane pyrimidine dimer, CPD.

Figure 4.

Figure 4.

Model of PrimPol-mediated replication fork progression. Distortion of DNA and base modification can be induced by various environmental insults and endogenous processes and, if not corrected prior to replication, can disrupt DNA synthesis by the cellular replicases (blue lines). A DNA modification on the leading strand is shown, which in this example has caused uncoupling of leading and lagging strand synthesis. This generates stretches of single-stranded DNA that will be coated by replication protein A (RPA), which in turn recruits PrimPol. PrimPol-dependent DNA or RNA synthesis (green lines) then facilitates restart of DNA replication. PrimPol may re-prime DNA synthesis downstream of the lesion leaving a daughter strand gap that can be subsequently filled by translesion synthesis (TLS) or homologous recombination (HR)-mediated processes. Alternatively, in the case of DNA lesions such as UV photoproducts (depicted in red lettering), PrimPol can use its TLS activity and directly extend the stalled primer terminus to synthesize DNA opposite the lesion, either alone or by cooperating with another DNA polymerase. For example, in the case of a template cyclobutane pyrimidine dimer (CPD), after incorporation of 2 terminal dA residues opposite the lesion, PrimPol can catalyze the extension of this mismatched terminus. In the case of a pyrimidine (6–4) pyrimidone photoproduct (6–4 PP), PrimPol can catalyze both the insertion of nucleotides opposite the damaged bases and the subsequent extension from the mismatched terminus, and thus could possibly catalyze complete bypass of this lesion. PrimPol misincorporates a dT opposite the 5′T of the lesion and either dG or dC opposite the 3′T, as shown in green.

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