ReviewDNA replication fidelity and cancer
Section snippets
Genetic instability and cancer
Tumor development is a multistep process requiring the accumulation of mutations that activate oncogenes or inactivate tumor suppressors [1], [2], [3]. To maintain normal cell functions, genetic stability is strictly controlled [4]. Therefore it is argued that defects in pathways governing genetic stability will facilitate tumorigenesis by fueling the reiterative process of mutation, selection and clonal expansion that drives cancer progression (reviewed and debated in [5], [6], [7], [8], [9],
Determinants of DNA replication fidelity
Normal cells replicate their DNA with extraordinary fidelity (∼10−10 mutations per base pair per cell division) [52]. This is achieved through the combined actions of polymerase base selectivity, 3′ → 5′ exonucleolytic proofreading, mismatch correction and DNA damage repair (Fig. 1; reviewed in [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71]).
Proofreading and MMR both contribute substantially to the overall fidelity of cellular DNA
Mutator mice
Although mechanisms of DNA replication fidelity have been studied extensively in simple microbes, less is known about the corresponding pathways and their functions in higher eukaryotes. Mammals require faithful DNA replication to avoid deleterious mutations in critical subpopulations of cells (gametes, stem cells, and developing embryos) and to sustain essential somatic functions throughout the adult reproductive life span. At the same time, increased mutation (hypermutation) is required for
Pol δ and ɛ mutations in human cancer
The studies of Pol δ and ɛ proofreading-deficient mice underscore the importance of DNA polymerase fidelity in the suppression of spontaneous tumorigenesis. It is reasonable to speculate that polymerase mutator alleles also increase the risk of human cancers [200], [201]. The mouse studies suggest roles for Pol ɛ mutators in the genesis of intestinal tumors and Pol δ mutators in skin and lung carcinogenesis. Pol ɛ and δ mutators are also implicated in hematologic malignancies, and aggressive
Summary and perspectives
At the beginning of the 20th century, cytogenetic techniques revealed the first chromosomal abnormalities in malignant cells and led to the hypothesis that genetic instability fueled cancer [230], [231]. Since then it has become clear that multiple changes in the genome, including point mutations, insertion/deletion events, large chromosomal rearrangements and epigenetic modifications of gene expression dysregulate cellular pathways on the road to malignant transformation [1], [2], [3], [13],
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
Our sincere thanks go to Larry Loeb for his critical insight and creative spirit. We also thank past and present laboratory members for valuable discussions and experimental contributions. Our research was supported by the National Institutes of Health (R01 ES09927, R01 CA098243, R01 CA111582, P20 CA103728, P01 AG01751 and P01 CA77852) and the National Institute of Environmental Health Sciences-sponsored Center for Ecogenetics and Environmental Health at the University of Washington (P30 ES07033
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2022, Journal of EthnopharmacologyCitation Excerpt :The genes activated after pretreated with GEB were involved in DNA repair and replication. First of all, Pole, Pole2 and Pole4, encode for DNA polymerase epsilon (POLE) subunits, and are considered to play a critical role in proofreading and correcting errors of DNA replication (Preston et al., 2010; Tabori et al., 2017). Furthermore, a set of mutations which affect the catalytic subunit of POLE has been found in various types of malignant neoplasms, including endometrial, colorectal, brain, stomach, breast, and pancreatic cancers (Campbell et al., 2017; Heitzer and Tomlinson, 2014; Cancer Genome Atlas Research Network, 2013; Palles et al., 2013; Shinbrot et al., 2014; Domingo et al., 2016).