title: Glycoxidative damage to human DNA: Neo-antigenic epitopes on DNA molecule could be a possible reason for autoimmune response in type 1 diabetes.
abstract: Advanced glycation end-products (AGEs) are known to be mutagenic, diabetogenic and vascular disease risk factors. Methylglyoxal (MG) is a dicarbonyl species that reacts with biological macromolecule (proteins, DNA and lipids) to give AGEs. Nonenzymatic glycation of MG with lysine (Lys) in the presence of copper (Cu(2+)) is reported to generate reactive oxygen species (ROS) capable of causing DNA damage. We show that DNA modification in MG-Lys-Cu(2+) system results in the generation of strand breaks, base modification, hyperchromicity and increased fluorescence intensity. Superoxide generation in the MG-Lys system was found to be significantly higher when compared with that in the MG and Lys alone. Moreover, d-penicillamine and pyridoxal phosphate significantly inhibited the formation of glycation products. The presence of a major DNA glycation adduct, N(2)-carboxyethyl-2'-deoxyguanosine (CEdG), was detected by high performance liquid chromatography (HPLC) and confirmed by nuclear magnetic resonance (NMR). As reported earlier, modified DNA (MG-Lys-Cu(2+)-DNA) was highly immunogenic in experimental animals. Furthermore, induced anti-MG-Lys-Cu(2+)-DNA antibodies were effective probe for detecting glycoxidative lesions in human genomic DNA of type I diabetes patients. Our results clearly imply that interaction of MG-Lys and Cu(2+) leads to the formation of AGEs and also the production of potent ROS, capable of causing DNA damage, thereby playing an important role in diabetes mellitus.
authors.affiliation: Department of Biochemistry, J.N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, India.
authors.forename: Saheem
authors.initials: S
authors.lastname: Ahmad
authors.lastname: Moinuddin
authors.forename: Uzma
authors.initials: U
authors.lastname: Shahab
authors.forename: Safia
authors.initials: S
authors.lastname: Habib
authors.forename: M
authors.initials: M
authors.lastname: Salman Khan
authors.forename: Khursheed
authors.initials: K
authors.lastname: Alam
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
mesh_terms: D015551:Autoimmunity; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010396:Penicillamine / Q000494:pharmacology; D011730:Pyridoxal / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000737:chemistry / Q000276:immunology
chemical_list: D000939:Epitopes; D017127:Glycation End Products, Advanced; C400382:N(2)-(1-carboxyethyl)deoxyguanosine; D011730:Pyridoxal; D011765:Pyruvaldehyde; D004247:DNA; D003849:Deoxyguanosine; D010396:Penicillamine
keywords: DNA; advanced glycation end-products; diabetes; glycation; methylglyoxal