DNA repair pathways and their implication in cancer treatment
ABSTRACT Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include strand breaks (double or single strand), crosslinks (inter-strand, intra-strand, DNA-protein crosslinks), and interference with nucleotide metabolism and DNA synthesis. On the other hand, cancer cells activate various DNA repair pathways and repair DNA damages induced by cytotoxic drugs. The purpose of the current review is to present the major types of DNA damage induced by cytotoxic agents, DNA repair pathways, and their role as predictive agents, as well as evaluate the future perspectives of the novel DNA repair pathways inhibitors in cancer therapeutics.
- SourceAvailable from: Sabine A S Langie
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- "The biological significance of both pathways is highlighted by the well-known association of BER or NER deficiency with the incidence of inherited (Cleaver et al., 2009) and sporadic types of cancer (Slyskova et al., 2012a). Moreover, the individual's BER and NER capacity is expected to have an influence on the response to anti-neoplastic drug treatment (Pallis and Karamouzis, 2010; Lord and Ashworth, 2012). Therefore, being able to screen an individual's repair capacity may represent a step toward risk assessment and individualized cancer therapy. "
ABSTRACT: Thousands of DNA lesions are estimated to occur in each cell every day and almost all are recognized and repaired. DNA repair is an essential system that prevents accumulation of mutations which can lead to serious cellular malfunctions. Phenotypic evaluation of DNA repair activity of individuals is a relatively new approach. Methods to assess base and nucleotide excision repair pathways (BER and NER) in peripheral blood cells based on modified comet assay protocols have been widely applied in human epidemiological studies. These provided some interesting observations of individual DNA repair activity being suppressed among cancer patients. However, extension of these results to cancer target tissues requires a different approach. Here we describe the evaluation of BER and NER activities in extracts from deep-frozen colon biopsies using an upgraded version of the in vitro comet-based DNA repair assay in which 12 reactions on one microscope slide can be performed. The aim of this report is to provide a detailed, easy-to-follow protocol together with results of optimization experiments. Additionally, results obtained by functional assays were analyzed in the context of other cellular biomarkers, namely single nucleotide polymorphisms and gene expressions. We have shown that measuring DNA repair activity is not easily replaceable by genomic or transcriptomic approaches, but should be applied with the latter techniques in a complementary manner. The ability to measure DNA repair directly in cancer target tissues might finally answer questions about the tissue-specificity of DNA repair processes and their real involvement in the process of carcinogenesis.Frontiers in Genetics 05/2014; 5:116. DOI:10.3389/fgene.2014.00116
DNA Repair and Human Health, 10/2011; , ISBN: 978-953-307-612-6
- "The defective function of one of the DNA repair pathways often results in overexpression of the other one. Increased processes of DNA repair may lead to resistance to cytostatics and radiotherapy (Pallis, Karamouzis 2010). The role of DNA damage and repair processes in pathogenesis and treatment of cancer was first noted in patients with inherited syndromes with defective DNA repair mechanisms such as Fanconi anemia. "
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ABSTRACT: DNA base-damage recognition in the base excision repair (BER) is a process operating on a wide variety of alkylated, oxidized and degraded bases. DNA glycosylases are the key enzymes which initiate the BER pathway by recognizing and excising the base damages guiding the damaged DNA through repair synthesis. We report here biochemical and structural evidence for the irreversible entrapment of DNA glycosylases by 5-hydroxy-5-methylhydantoin, an oxidized thymine lesion. The first crystal structure of a suicide complex between DNA glycosylase and unrepaired DNA has been solved. In this structure, the formamidopyrimidine-(Fapy) DNA glycosylase from Lactococcus lactis (LlFpg/LlMutM) is covalently bound to the hydantoin carbanucleoside-containing DNA. Coupling a structural approach by solving also the crystal structure of the non-covalent complex with site directed mutagenesis, this atypical suicide reaction mechanism was elucidated. It results from the nucleophilic attack of the catalytic N-terminal proline of LlFpg on the C5-carbon of the base moiety of the hydantoin lesion. The biological significance of this finding is discussed.Nucleic Acids Research 04/2011; 39(14):6277-90. DOI:10.1093/nar/gkr215 · 9.11 Impact Factor