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Endogenously generated DNA nucleobase modifications source,and significance as possible biomarkers of malignant transformation risk,and role in anticancer therapy
Authors:Ryszard Olinski  Daniel Gackowski  Marcus S Cooke
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
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.
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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