Endogenously generated DNA nucleobase modifications source,and significance as possible biomarkers of malignant transformation risk,and role in anticancer therapy |
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Authors: | Ryszard Olinski Daniel Gackowski Marcus S Cooke |
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Institution: | 1. Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karlowicza 24, 85-095 Bydgoszcz, Poland;2. Oxidative Stress Group, Department of Environmental Health Sciences, Florida International University, Modesto A. Maidique Campus, AHC5 355 11200 SW 8th Street, Miami, FL 33199, United States;3. Biomolecular Sciences Institute, Florida International University, United States |
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Abstract: | The DNA of all living cells undergoes continuous structural and chemical alteration, which may be derived from exogenous sources, or endogenous, metabolic pathways, such as cellular respiration, replication and DNA demethylation. It has been estimated that approximately 70,000 DNA lesions may be generated per day in a single cell, and this has been linked to a wide variety of diseases, including cancer. However, it is puzzling why potentially mutagenic DNA modifications, occurring at a similar level in different organs/tissue, may lead to organ/tissue specific cancers, or indeed non-malignant disease – what is the basis for this differential response? We suggest that it is perhaps the precise location of damage, within the genome, that is a key factor. Finally, we draw attention to the requirement for reliable methods for identification and quantification of DNA adducts/modifications, and stress the need for these assays to be fully validated. Once these prerequisites are satisfied, measurement of DNA modifications may be helpful as a clinical parameter for treatment monitoring, risk group identification and development of prevention strategies. |
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Keywords: | ROS reactive oxygen species 8-oxoGua 8-Oxo-7 8-dihydroguanine UNG uracil-DNA glycosylase TET ten-eleven translocation protein 5-mCyt 5-Methylcytosine 5-hmCyt 5-Hydroxymethylcytosine 5-fCyt 5-formylcytosine 5-caCyt 5-Carboxycytosine BER base excision repair TDG thymine DNA glycosylase 5-hmUra 5-hydroxymethylUra AID Activation-induced cytosine deaminase MMR mismatch repair dUTPase deoxyuridine-triphosphatase SHM somatic hypermutation MMR mismatch repair ESCODD European Standards Committee on Oxidative DNA Damage dN deoxuynucleosides OGG1 8-Oxoguanine DNA glycosylase 1 8-oxodG 8-oxo-7 8-dihydro-2'deoxyguanosine LSD1 lysine-specific demethylase 1 SMUG single-strand-specific monofunctional uracil DNA glycosylase AML acute myeloid leukemia HSC hematopoietic stem cells 2D–UPLC-MS/MS two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry DNA damage DNA repair Biomarkers Methylation Oxidative stress 8-Oxo-7 8-dihydroguanine 5-Hydroxymethylcytosine 5-Formylcytosine 5-Carboxycytosine 5-Hydroxymethyluracil Cancer |
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