Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function-Reference-Cited by-同舟云学术

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Published:2022-06-24 Issue:6600 Volume:376 Page:1471-1476
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Michel Maurice¹^ORCID,Benítez-Buelga Carlos¹²,Calvo Patricia A.³,Hanna Bishoy M. F.¹^ORCID,Mortusewicz Oliver¹^ORCID,Masuyer Geoffrey⁴⁵^ORCID,Davies Jonathan⁵^ORCID,Wallner Olov¹^ORCID,Sanjiv Kumar¹^ORCID,Albers Julian J.¹^ORCID,Castañeda-Zegarra Sergio¹⁶^ORCID,Jemth Ann-Sofie¹^ORCID,Visnes Torkild⁷^ORCID,Sastre-Perona Ana⁸^ORCID,Danda Akhilesh N.¹,Homan Evert J.¹^ORCID,Marimuthu Karthick¹,Zhenjun Zhao¹^ORCID,Chi Celestine N.⁹,Sarno Antonio¹⁰^ORCID,Wiita Elisée¹,von Nicolai Catharina¹^ORCID,Komor Anna J.¹¹^ORCID,Rajagopal Varshni¹,Müller Sarah¹^ORCID,Hank Emily C.¹^ORCID,Varga Marek¹^ORCID,Scaletti Emma R.⁵¹²^ORCID,Pandey Monica¹¹³^ORCID,Karsten Stella¹^ORCID,Haslene-Hox Hanne⁷,Loevenich Simon⁷^ORCID,Marttila Petra¹^ORCID,Rasti Azita¹,Mamonov Kirill¹^ORCID,Ortis Florian¹^ORCID,Schömberg Fritz¹⁴^ORCID,Loseva Olga¹,Stewart Josephine¹,D’Arcy-Evans Nicholas¹,Koolmeister Tobias¹,Henriksson Martin¹,Michel Dana¹⁵,de Ory Ana¹⁶,Acero Lucia⁸^ORCID,Calvete Oriol¹⁷^ORCID,Scobie Martin¹^ORCID,Hertweck Christian¹¹¹⁸^ORCID,Vilotijevic Ivan¹⁴^ORCID,Kalderén Christina¹^ORCID,Osorio Ana¹⁷¹⁹^ORCID,Perona Rosario²¹⁹^ORCID,Stolz Alexandra²⁰^ORCID,Stenmark Pål⁵¹²^ORCID,Berglund Ulrika Warpman¹^ORCID,de Vega Miguel³^ORCID,Helleday Thomas¹¹³^ORCID

Affiliation:

1. Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.

2. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), 28029 Madrid, Spain.

3. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain.

4. Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK.

5. Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.

6. Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway.

7. Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7465 Trondheim, Norway.

8. Experimental Therapies and Novel Biomarkers in Cancer, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.

9. Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

10. Department of Environment and New Resources, SINTEF Ocean, N-7496 Trondheim, Norway.

11. Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Department of Biomolecular Chemistry, 07745 Jena, Germany.

12. Department of Experimental Medical Science, Lund University, Lund, Sweden.

13. Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.

14. Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, 07743 Jena, Germany.

15. Chemical Processes and Pharmaceutical Development, Unit Process Chemistry I, Research Institutes of Sweden – RISE, 151 36 Södertälje, Sweden.

16. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.

17. Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.

18. Institute of Microbiology, Friedrich-Schiller-University Jena, 07743 Jena, Germany.

19. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.

20. Institute of Biochemistry II and Buchmann Institute for Molecular Life Science, Goethe University Frankfurt, 60590 Frankfurt, Germany.

Abstract

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 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference29 articles.

1. Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1)

2. Potent and Selective Inhibitors of 8-Oxoguanine DNA Glycosylase

3. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

4. Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention

5. The activity of the DNA repair enzyme hOGG1 can be directly modulated by ubiquinol

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