Biology subjects

Dizdaroglu, M.

Publications and source records attributed to Dizdaroglu, M..

3 recordsLinked to original sources

bioRxiv2026

Small molecule agonists of 8-oxoguanine DNA glycosylase, OGG1

Base excision repair (BER) is the primary pathway that removes oxidatively-induced DNA base damage from the nuclear and mitochondrial genomes, with 8-oxoguanine DNA glycosylase (OGG1) initiating repair at the two most frequently-formed base lesions: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoGua) and 2,6-diamino-4-oxo-5-formamidopyrimidine (FapyGua). Humans expressing a catalytically-compromised variant of OGG1 (S326C) are at increased risk for type 2 diabetes, Alzheimers disease, and Parkinsons disease. To potentially enhance the overall catalytic efficiency of this variant, a prior medicinal chemistry screen discovered seven chemically distinct agonists of OGG1 that stimulated activity in vitro and attenuated a paraquat (PQ) challenge in cultured cells. Herein, we developed structure-activity relationships around one specific core structure, F01. Using fluorescence-based DNA cleavage assays, we assessed the abilities of these compounds to stimulate the overall rate of OGG1 catalysis. Multiple compounds were identified that increased OGG1 activity on DNAs containing a site-specific 8-oxoGua by 2-fold or greater, with 9 compounds showing EC50 concentrations lower than F01 and were specific for OGG1. Selected agonists were shown to enhance OGG1-catalyzed release of 8-oxoGua and FapyGua from {gamma}-irradiated high-molecular-weight DNA using gas chromatography tandem mass spectrometry analyses. Since these assays did not reveal which step in the overall reaction was stimulated, we used a separation-of-function OGG1 mutant that possessed glycosylase, but not abasic-site (AP) lyase activity to demonstrate that the glycosylase step was not enhanced. In contrast, all agonists stimulated the AP lyase activity to levels equal to or greater than the magnitude of stimulation observed for overall chemistry, implicating agonist-mediated turnover as a potential contributor to the overall rate stimulation. The biological activities of selected agonists were evaluated in OGG1-deficient Kasumi-1 cells under conditions of paraquat (PQ)-induced oxidative stress, with several compounds mitigating PQ challenge.

biochemistry↗

bioRxiv2025

DNA Content and DNA Damage in Raw and Heat-processed Foods

DNA in foods is a source of nucleotides that are salvaged by tissues as building blocks for chromosomal and mitochondrial DNA. A recent study provided preliminary evidence that high-temperature cooking damages the DNA in foods and suggested that certain forms of DNA damage can be taken up as nucleotides via metabolic salvage in cells and animals, directly incorporating genotoxic and mutagenic species into the host DNA. To assess potential risks, we surveyed DNA in 21 food ingredients, including plant- and meat-based foods in raw and roasted form. We find large variation in extractable DNA content, implying widely variable levels of consumption. Cooking resulted in greatly elevated levels of oxidative and deaminated DNA damage in nearly all foods as indicated by 8-oxo-dG and dU nucleotides; with up to 250-fold increases. Studies of human cell lines found that incubation with these damaged nucleosides resulted in cytotoxicity and increased DNA double-strand break levels.

biochemistry↗

bioRxiv2017

Ectopic Expression of DNA Repair Enzymes Modulates Survival following Ultraviolet Irradiation Challenge

In Escherichia coli, the nucleotide excision repair (NER) pathway removes ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) and 6-4 dipyrimidine photoproducts (6-4 PPs). Activation of alternative repair pathways, such as base excision repair (BER) and nucleotide incision repair (NIR), is inoperative because this organism lacks both the necessary BER DNA glycosylase and NIR UV endonuclease to initiate repair of these lesions. To determine if initiation of either pathway would enhance survival to biologically-relevant UV irradiation, the BER and NIR pathways were activated by expression of Chlorella virus-1 pyrimidine dimer glycosylase (cv-pdg) and Schizosaccharomyces pombe UV endonuclease (UVDE), respectively. The substrate specificity of cv-pdg includes CPDs and ring-fragmented purines, 4,6-diamino-5-formamidopyrimidine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine, but not 6-4 PPs. In contrast, while UVDE incises DNA containing CPDs and 6-4 PPs, it was not previously known if the substrate specificity of UVDE included DNA containing ring-fragmented purines. Mass spectrometry was used to establish that these oxidatively-induced lesions were not substrates for UVDE. Expression of either cv-pdg or UVDE in NER-deficient E. coli significantly enhanced survival following UVB irradiation, but not to the levels of wild type (WT) cells. Survival of NER-proficient, homologous recombination-deficient cells could also be significantly enhanced by expression of either enzyme, suggesting that in response to UVB exposure, interactions between NER and activated BER or NIR pathways could be additive. Further, expression of cv-pdg or UVDE in WT E. coli enhanced survival following solar-simulated light (SSL) exposures.

microbiology↗