8-oxoG DNA glycosylase OGG1 activator that induced β,δ-lyase activity for polynucleotide kinase phosphatase (PNKP1)-dependent base excision repair (BER).
TH10785 is an 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1) activator that interats with OGG1 via Phe319 and Gly42, causing increased OGG1 recruitment to cellular oxidative DNA damage sites (by 1.37-fold post 20 sec 1 µM treatment; U2OS). TH10785-activated OGG1 recognizes not only 8-oxoG, but also apurinic/apyrimidinic (AP, abasic) sites with a higher efficiency due to a newly induced β,δ-lyase enzymatic activity that generates base excision repair (BER) intermediates that require polynucleotide kinase phosphatase (PNKP1) instead of apurinic endonuclease 1 (APE1) for completing the repair.
The common oxidatively generated lesion, 8-oxo-7,8-dihydroguanine (8-oxoGua), is removed from DNA by base excision repair. The glycosylase primarily charged with recognition and removal of this lesion is 8-oxoGuaDNA glycosylase 1 (OGG1). When left unrepaired, 8-oxodG alters transcription and is mutagenic.
A "Failed" Assay Development for the Discovery of Rescuing Small Molecules from the Radiation Damage
Science (New York, N.Y.), 376(6600), 1471-1476 (2022-06-24)
Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42
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