DNA repair pathways and their implication in cancer treatment

Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece.
CANCER AND METASTASIS REVIEW (Impact Factor: 7.23). 12/2010; 29(4):677-85. DOI: 10.1007/s10555-010-9258-8
Source: PubMed


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.

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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. "
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    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
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    • "The principal mechanisms of DSB repair in mammalian cells include nonhomologous end-joining (NHEJ) and homologous recombination repair (HR). HR ensures accurate DSB repair, while NHEJ repair is rapid and efficient but error-prone [13,14]. "
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    ABSTRACT: Background The DNA damage-mediated cell cycle checkpoint is an essential mechanism in the DNA damage response (DDR). During embryonic development, the characteristics of cell cycle and DNA damage checkpoint evolve from an extremely short G1 cell phase and lacking G1 checkpoint to lengthening G1 phase and the establishment of the G1 checkpoint. However, the regulatory mechanisms governing these transitions are not well understood. In this study, pregnant mice were exposed to ionizing radiation (IR) to induce DNA damage at different embryonic stages; the kinetics and mechanisms of the establishment of DNA damage-mediated G1 checkpoint in embryonic liver were investigated. Results We found that the G2 cell cycle arrest was the first response to DNA damage in early developmental stages. Starting at E13.5/E15.5, IR mediated inhibition of the G1 to S phase transition became evident. Concomitantly, IR induced the robust expression of p21 and suppressed Cdk2/cyclin E activity, which might involve in the initiation of G1 checkpoint. The established G1 cell cycle checkpoint, in combination with an enhanced DNA repair capacity at E15.5, displayed biologically protective effects of repairing DNA double-strand breaks (DSBs) and reducing apoptosis in the short term as well as reducing chromosome deletion and breakage in the long term. Conclusion Our study is the first to demonstrate the establishment of the DNA damage-mediated G1 cell cycle checkpoint in liver cells during embryogenesis and its in vivo biological effects during embryonic liver development.
    BMC Developmental Biology 05/2014; 14(1):23. DOI:10.1186/1471-213X-14-23 · 2.67 Impact Factor
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    • "The DDR assesses the scope and severity of DNA damage to initiate cell cycle arrest, senescence, repair, or in the case of irreparable damage, apoptosis. If repair is activated then a number of different repair mechanisms can be engaged [reviewed in Ref. (9)]. Small lesions of damaged or incorrectly inserted nucleotides are repaired by base excision repair (BER), nucleotide excision repair (NER), or mismatch repair (MMR). "
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    ABSTRACT: Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR) and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1, and p53 and the feedback on estrogen receptor signaling from these proteins. We put forward the hypothesis that estrogen receptor signaling converges to suppress effective DNA repair and apoptosis in favor of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer, which will further change the processing of DNA damage. Finally, the action of estrogen signaling on DNA damage is also relevant to the therapeutic setting as the suppression of a DDR by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.
    Frontiers in Oncology 05/2014; 4:106. DOI:10.3389/fonc.2014.00106
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