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

Hank, Emily C. ; D’Arcy-Evans, Nicholas D. ; Scaletti, Emma Rose ; Benítez-Buelga, Carlos ; Wallner, Olov ; Ortis, Florian ; Zhou, Kaixin ; Meng, Liuzhen ; del Prado, Alicia and Calvo, Patricia , et al. (2026) In RSC Chemical Biology 7(1). p.169-181
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... (More)

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-d]-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 de novo 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
RSC Chemical Biology
volume
7
issue
1
pages
13 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:105027550859
  • pmid:41195166
ISSN
2633-0679
DOI
10.1039/d4cb00323c
language
English
LU publication?
yes
id
68ec567c-d3e0-4db4-87d5-1e5a428a4e0a
date added to LUP
2026-03-16 10:53:27
date last changed
2026-07-08 07:26:35
@article{68ec567c-d3e0-4db4-87d5-1e5a428a4e0a,
  abstract     = {{<p>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-d]-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 de novo 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.</p>}},
  author       = {{Hank, Emily C. and D’Arcy-Evans, Nicholas D. and Scaletti, Emma Rose and Benítez-Buelga, Carlos and Wallner, Olov and Ortis, Florian and Zhou, Kaixin and Meng, Liuzhen and del Prado, Alicia and Calvo, Patricia and Almlöf, Ingrid and Wiita, Elisée and Nierlin, Karen and Košenina, Sara and Krämer, Andreas and Eddershaw, Alice and Kehler, Mario and Long, Maeve and Jemth, Ann Sofie and Dawson, Holly and Stewart, Josephine and Dickey, Adam and Astorga, Mikhael E. and Varga, Marek and Homan, Evert J. and Scobie, Martin and Knapp, Stefan and Sastre, Leandro and Stenmark, P. and de Vega, Miguel and Helleday, Thomas and Michel, Maurice}},
  issn         = {{2633-0679}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{169--181}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{RSC Chemical Biology}},
  title        = {{Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1}},
  url          = {{http://dx.doi.org/10.1039/d4cb00323c}},
  doi          = {{10.1039/d4cb00323c}},
  volume       = {{7}},
  year         = {{2026}},
}