Abstract
Simple SummaryThe etiology of cancer is linked to the occurrence of mutations during the reduplication of genetic material. Mutations leading to low replication fidelity are the culprits of many hereditary and sporadic cancers. The archetype of the current model of replication fork was proposed 30 years ago. In the sequel to our 2010 review with the words “years after” in the title inspired by A. Dumas’s novels, we go over new developments in the DNA replication field and analyze how they help elucidate the effects of the genetic variants of DNA polymerases on cancer.Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication fork organization. The principal idea of participation of different polymerases in specific transactions at the fork proposed by Morrison and coauthors 30 years ago and later named “division of labor,” remains standing, with an amendment of the broader role of polymerase δ in the replication of both the lagging and leading DNA strands. However, cancer-associated mutations predominantly affect the catalytic subunit of polymerase ε that participates in leading strand DNA synthesis. We analyze how new findings in the DNA replication field help elucidate the polymerase variants’ effects on cancer.
Highlights
Because three fidelity steps occur in a series, a combination of defects in any of the two consecutive steps results in multiplicative, more than a 1000-fold increase of mutation rates, up to levels that are incompatible with the life of haploids: exo− pol ε or pol δ with MMR defect (MMR- ) [21]; exo- pol ε with exo- pol δ [24,25]; relaxed base selectivity of pol α, or pol ε, or pol δ with MMR- [15,26,27]; and low base selectivity of pols ε or δ with their proofreading defects [25,28]
In 1990, a Cell paper described the discovery of the third replicative DNA polymerase, pol ε in yeast [29], and a paper in the Proceeding of the National Academy of U.S.A. characterized pol ε purified from HeLa cells [30]
Along with further progress and accuracy in the characterization of tumor genomes and functional characterization of recurrent mutations, new regions of DNA pols catalytic and other subunits whose alterations predispose to cancer will be found
Summary
Research in the past decade has revealed the lofty role of alterations in replicative DNA polymerases (pols) in sporadic and hereditary cancer [1,2]. The alterations in the proofreading exonuclease domain caused by mutations in the POLE gene (see Table 1 for the nomenclature of DNA polymerase subunits in humans and in yeast and mouse models) are proven to be causative factors in the etiology of the malignant transformation (Figure 1), with predominant, but not exclusive prevalence, in colon and endometrial cancers. In POL1, REV3L, and the C-terminal half of POLE, the exonuclease motifs are inactivated during evolution; they are shown in blue. Inactivated pol motifs in the C-terminal half of POLE are shown in black. The key for these and other elements of the pol primary structure is in the left upper quarter of the figure. Rows of circles of different sizes and shades of grey below the catalytic pol subunits represent the number of missense mutations found in tumors along the protein regions in 100 amino acid increments. A guide explaining the relation between size and intensity of grey to the number of mutations found in the database in the 100 amino acids interval is on the left lower quarter of the figure
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