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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
Authors:
Maurice
Michel
(Karolinska Institutet)
,
Carlos
Benítez-Buelga
(Karolinska Institutet; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM)
,
Patricia A.
Calvo
(Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM))
,
Bishoy M. F.
Hanna
(Karolinska Institutet)
,
Oliver
Mortusewicz
(Karolinska Institutet)
,
Geoffrey
Masuyer
(University of Bath; Stockholm University)
,
Jonathan
Davies
(Stockholm University)
,
Olov
Wallner
(Karolinska Institutet)
,
Sanjiv
Kumar
(KTH Royal Institute of Technology)
,
Julian J.
Albers
(Karolinska Institutet)
,
Sergio
Castañeda-Zegarra
(Karolinska Institutet; Norwegian University of Science and Technology)
,
Ann-Sofie
Jemth
(Karolinska Institutet)
,
Torkild
Visnes
(SINTEF Industry)
,
Ana
Sastre-Perona
(Hospital La Paz Institute for Health Research (IdiPAZ))
,
Akhilesh N.
Danda
(Karolinska Institutet)
,
Evert J.
Homan
(Karolinska Institutet)
,
Karthick
Marimuthu
(Karolinska Institutet)
,
Zhao
Zhenjun
(Karolinska Institutet)
,
Celestine N.
Chi
(Uppsala University)
,
Antonio
Sarno
(SINTEF Ocean)
,
Elisée
Wiita
(Karolinska Institutet)
,
Catharina
Von Nicolai
(Karolinska Institutet)
,
Anna J.
Komor
(Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute)
,
Varshni
Rajagopal
(Karolinska Institutet)
,
Sarah
Müller
(Karolinska Institutet)
,
Emily C.
Hank
(Karolinska Institutet)
,
Marek
Varga
(Karolinska Institutet)
,
Emma R.
Scaletti
(Stockholm University; Lund University)
,
Monica
Pandey
(Karolinska Institutet; University of Sheffield)
,
Stella
Karsten
(Karolinska Institutet)
,
Hanne
Haslene-Hox
(SINTEF Industry)
,
Simon
Loevenich
(SINTEF Industry)
,
Petra
Marttila
(Karolinska Institutet)
,
Azita
Rasti
(Karolinska Institutet)
,
Kirill
Mamonov
(Karolinska Institutet)
,
Florian
Ortis
(Karolinska Institutet)
,
Fritz
Schömberg
(Friedrich Schiller University Jena)
,
Olga
Loseva
(Karolinska Institutet)
,
Josephine
Stewart
(Karolinska Institutet)
,
Nicholas
D’arcy-Evans
(Karolinska Institutet)
,
Tobias
Koolmeister
(Karolinska Institutet)
,
Martin
Henriksson
(Karolinska Institutet)
,
Dana
Michel
(Research Institutes of Sweden – RISE)
,
Ana
De Ory
(Stockholm University)
,
Lucia
Acero
(Hospital La Paz Institute for Health Research (IdiPAZ))
,
Oriol
Calvete
,
Martin
Scobie
(Karolinska Institutet)
,
Christian
Hertweck
(Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute; Friedrich-Schiller-University Jena)
,
Ivan
Vilotijevic
(Friedrich Schiller University Jena)
,
Christina
Kalderén
(Karolinska Institutet)
,
Ana
Osorio
(Spanish National Cancer Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)Research Centre (CNIO);)
,
Rosario
Perona
(Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))
,
Alexandra
Stolz
(Goethe University Frankfurt)
,
Pal
Stenmark
(Stockholm University; Lund University)
,
Ulrika
Warpman Berglund
(Karolinska Institutet)
,
Miguel
De Vega
(Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM))
,
Thomas
Helleday
(Karolinska Institutet; University of Sheffield)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Science
, VOL 376
, PAGES 1471 - 1476
State:
Published (Approved)
Published:
June 2022
Diamond Proposal Number(s):
15806
,
21625
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.
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I04-Macromolecular Crystallography
Added On:
29/06/2022 08:47
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Biochemistry
Catalysis
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)