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

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.

Category

Academic article

Language

English

Author(s)

  • Maurice Michel
  • Carlos Benítez-Buelga
  • Patricia Calvo
  • Bishoy Magdy Fekry Hanna
  • Oliver Mortusewicz
  • Geoffrey Masuyer
  • Jonathan Davies
  • Olov Wallner
  • Kumar Sanjiv
  • Julian J. Albers
  • Sergio Miguel Castaneda Zegarra
  • Ann-Sofie Jemth
  • Torkild Visnes
  • Ana Sastre-Perona
  • Akhilesh Nagesh Danda
  • Homan Evert J
  • Karthick Marimuthu
  • Zhao Zhenjun
  • Celestine N. Chi
  • Antonio Sarno
  • Elisée Wiita
  • Catharina Von Nicolai
  • Anna J. Komor
  • Varshni Rajagopal
  • Sarah Müller
  • Emily C. Hank
  • Marek Varga
  • Emma R. Scaletti
  • Monica Pandey
  • Stella Karsten
  • Hanne Haslene-Hox
  • Simon Loevenich
  • Petra Marttila
  • Azita Rasti
  • Kirill Mamonov
  • Florian Ortis
  • Fritz Schömberg
  • Olga Loseva
  • Josephine Stewart
  • Nicholas D’Arcy-Evans
  • Tobias Koolmeister
  • Martin Henriksson
  • Dana Michel
  • Ana de Ory
  • Lucia Acero
  • Oriol Calvete
  • Martin Scobie
  • Christian Hertweck
  • Ivan Vilotijevic
  • Christina Kalderén
  • Ana Osorio
  • Rosario Perona
  • Alexandra Stolz
  • Pål Stenmark
  • Ulrika Warpman Berglund
  • Miguel de Vega
  • Thomas Helleday

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • SINTEF Ocean / Fisheries and New Biomarine Industry
  • Karolinska Institutet
  • Lund University
  • Stockholm University
  • Uppsala University
  • RISE Research Institutes of Sweden
  • Spain
  • Spanish National Research Council
  • Carlos III Health Institute
  • Spanish National Cancer Research Centre
  • University of Bath
  • University of Sheffield
  • Germany
  • Friedrich Schiller University of Jena
  • Johann Wolfgang Goethe University of Frankfurt am Main
  • Norwegian University of Science and Technology

Year

2022

Published in

Science

ISSN

0036-8075

Volume

376

Issue

6600

Page(s)

1471 - 1476

View this publication at Norwegian Research Information Repository