Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Brønsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-<i>d</i>]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a <i>de novo</i> OGG1 β-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported β,δ-lyase stimulator TH10785.

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Journal
RSC Chemical Biology
Published
2025-10-28
DOI
https://doi.org/10.1039/d4cb00323c
Primary Topic
DNA Repair Mechanisms
Type
article
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article

Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

Ann‐Sofie Jemth, Stefan Knapp, Evert J. Homan, Alicia del Prado et al.
RSC Chemical Biology
DNA Repair Mechanisms
article

Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

Ann‐Sofie Jemth, Stefan Knapp, Evert J. Homan, Alicia del Prado, Kaixin Zhou, Miguel de Vega, Marek Varga, Emily C. Hank, Thomas Helleday, Pål Stenmark, Josephine Stewart, Nicholas D. D’Arcy-Evans, Emma Rose Scaletti, Olov A. Wallner, Alice Eddershaw, Holly Dawson, Leandro Sastre, Maurice Michel, Maeve Long, Carlos Benitéz‐Buelga, Martin Scobie, Sara Košenina, Ingrid Almlöf, Elisée Wiita, Andreas Krämer, Florian Ortis, Patricia Calvo, Adam Dickey, Mikhael E. Astorga, Liuzhen Meng, Mario Kehler, Karen Nierlin
article en

Abstract

Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Brønsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-<i>d</i>]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a <i>de novo</i> OGG1 β-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported β,δ-lyase stimulator TH10785.

RSC Chemical BiologyVol. 7(1)
Goethe University Frankfurt (DE), Karolinska University Hospital (SE), Stockholm University (SE), Lund University (SE), Instituto de Salud Carlos III (ES), Weston Park Cancer Centre (GB), Structural Genomics Consortium (CA), Karolinska Institutet (SE), Instituto de Investigaciones Biomédicas Sols-Morreale (ES), Centro de Biología Molecular Severo Ochoa (ES), Instituto de Investigación de Enfermedades Raras (ES), Universidad Autónoma de Madrid (ES)
McGill University, Diamond Light Source, European Federation of Pharmaceutical Industries and Associations, European Commission, Cancerfonden, Karolinska Institutet, Novo Nordisk, Kungliga Tekniska Högskolan, Vetenskapsrådet, Goethe-Universität Frankfurt am Main, Novo Nordisk Fonden, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Openalex Percentile: Top 72%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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