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Review
. 2010 Oct;20(5):281-93.
doi: 10.1016/j.semcancer.2010.10.009. Epub 2010 Oct 15.

DNA Replication Fidelity and Cancer

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Free PMC article
Review

DNA Replication Fidelity and Cancer

Bradley D Preston et al. Semin Cancer Biol. .
Free PMC article

Abstract

Cancer is fueled by mutations and driven by adaptive selection. Normal cells avoid deleterious mutations by replicating their genomes with extraordinary accuracy. Here we review the pathways governing DNA replication fidelity and discuss evidence implicating replication errors (point mutation instability or PIN) in carcinogenesis.

Figures

Fig. 1
Fig. 1
Determinants of DNA replication fidelity. Schematic of a DNA replication fork with Pol ε and Pol δ on the leading- and lagging-strands, respectively. Major determinants of faithful DNA synthesis are highlighted in yellow. The polymerase domains (POL) of Pols ε and δ discriminate between correct and incorrect dNTPs prior to phosphodiester bond formation. If an error occurs, these are corrected primarily by the intrinsic proofreading exonuclease (EXO) present in each polymerase. Errors that escape proofreading are rectified by mismatch repair (MMR), which acts on both lagging (shown here) and leading (not shown) strands. DNA damage repair and dNTP pool ratios also influence replication fidelity.
Fig. 2
Fig. 2
Pathways correcting DNA polymerase errors. During DNA synthesis, rare polymerase errors [base•base mispairs (left) or primer•template slippage (right)] impede primer extension and thus trigger transfer of the growing DNA strand from the polymerase active site POL) to the 3′→5′ exonuclease active site (EXO) where the errant bases are excised by proofreading. Errors that escape 3′→5′ exonucleolytic proofreading are corrected, at least in part, by two partially redundant pathways of the MMR system. Studies in yeast indicate that Pol proofreading and MMR act in series along a common pathway [75, 76]. MutSα and MutSβ have overlapping substrate specificities, and MutSα also recognizes DNA damage and signals apoptosis. [Note: mammalian Pms2 (shown here) is equivalent to yeast Pms1.]
Fig. 3
Fig. 3
DNA “lesions” arising spontaneously in mammalian cells. (A) Spontaneous chemical decay of deoxyribonucleic acid. Rates are expressed as the number of decay events estimated to occur per mammalian cell per day under physiological conditions ([97, 98]; T. Lindahl, personal communication). (B) Distribution of DNA lesions formed per cell per day in dividing mammaliaan cells. Values for hydrolysis, oxidation and methylation products are from panel A. Polymerase errors (100,000 or more per cell division) are based on measurements of Pol δ and Pol ε error rates in vitro in the absence of proofreading as described in the text and footnote 1. This assumes that actively dividing cells replicate approximately once every 24 hours. Shorter or longer cell cycles will occur in vivo depending on cell type, tissue, stage of embryonic development, and responses to environmental conditions. Panel B shows the distribution when there are 100,000 polymerase errors per day, but this could be as high as 1,000,000 errors per day (see footnote 1).
Fig. 4
Fig. 4
Survival and cancer phenotypes of Pol δ and Pol ε proofreading-deficient mice. (A) Kaplan-Meier survival estimates. Mice were followed for long-term survival and observed daily until moribund or unexpected natural death. dark red, Polee/e (n=36) and Pole+/e (n=35) in C57BL/6 genetic background after removal of the neomycin selection cassette (Neo); light red, Polee/e (n=35) and Pole+/e (n=45) in a mixed C57BL/6:129/Sv genetic background with the neomycin selection cassette still present (Neo+); blue, Pold1e/e (n=40) in C57BL/6 (Neo); purple, Polee/ePold1e/e (n=35) in C57BL/6 (Neo); black, wild-type (WT; n=37) C57BL/6; green, Mlh1Δ/Δ (n=27) in C57BL/6. One month = 30.4 days. (B) Spontaneous tumor incidences. Moribund mice were euthanized and necropsied, and tumors were diagnosed by histology. *Incidences among 32 wild-type (WT), 33 Polee/e, 36 Pold1e/e, 26 Mlh1Δ/Δ and 34 Polee/ePold1e/e mice. Tumors with ≥15% incidence in one or more groups. Figure from Albertson et al. [83].
Fig. 5
Fig. 5
Pol δ and Pol ε amino acid changes encoded by human SNPs and found in tumor cells. Alignment of human Pol δ and Pol ε (H.s. Pol d and H.s. Pol e, respectively). To generate this alignment, yeast and human Pol δ and ε sequences were first aligned as described [205], and conserved amino acid residues were highlighted as follows: red, absolutely conserved among the four sequences; yellow, identical in the majority of sequences; gray, similar in majority of sequences. Yeast sequences were then remove from the figure for clarity. Conserved polymerase and exonuclease motifs are indicated by colored frames: blue, exonuclease motifs; green, polymerase motifs [204]. The zinc finger in Pol ε (residues 2146–2246) is underlined with component cysteines highlighted in green. Amino acid changes encoded by SNPs are placed above (Pol δ, black) or below (Pol ε, cyan) the alignment at the relevant positions. Data are from the NCBI dbSNP (www.ncbi.nlm.nih.gov/SNP) and NIEHS geneSNP (www.genome.utah.edu/genesnps) databases. Pol δ changes found in human colorectal cancer cell lines or primary tumors [214, 215] are highlighted in gray above the Pol δ sequence. Asterisk (*) marks the amino acid substitution found in rat Novikoff hepatoma cells (rat R648Q equivalent to human R652Q [216]).

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