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

被引：47

作者：

Michel, Maurice ^{[1
]}

Benitez-Buelga, Carlos ^{[1
,2
]}

Calvo, Patricia A. ^{[3
]}

Hanna, Bishoy M. F. ^{[1
]}

Mortusewicz, Oliver ^{[1
]}

Masuyer, Geoffrey ^{[4
,5
]}

Davies, Jonathan ^{[5
]}

Wallner, Olov ^{[1
]}

Sanjiv, Kumar ^{[1
]}

Albers, Julian J. ^{[1
]}

Castaneda-Zegarra, Sergio ^{[1
,6
]}

Jemth, Ann-Sofie ^{[1
]}

Visnes, Torkild ^{[7
]}

Sastre-Perona, Ana ^{[8
]}

Danda, Akhilesh N. ^{[1
]}

Homan, Evert J. ^{[1
]}

Marimuthu, Karthick ^{[1
]}

Zhao Zhenjun ^{[1
]}

Chi, Celestine N. ^{[9
]}

Sarno, Antonio ^{[10
]}

Wiita, Elisee ^{[1
]}

von Nicolai, Catharina ^{[1
]}

Komor, Anna J. ^{[11
]}

Rajagopal, Varshni ^{[1
]}

Muller, Sarah ^{[1
]}

Hank, Emily C. ^{[1
]}

Varga, Marek ^{[1
]}

Scaletti, Emma R. ^{[5
,12
]}

Pandey, Monica ^{[1
,13
]}

Karsten, Stella ^{[1
]}

Haslene-Hox, Hanne ^{[7
]}

Loevenich, Simon ^{[7
]}

Marttila, Petra ^{[1
]}

Rasti, Azita ^{[1
]}

Mamonov, Kirill ^{[1
]}

Ortis, Florian ^{[1
]}

Schoemberg, Fritz ^{[14
]}

Loseva, Olga ^{[1
]}

Stewart, Josephine ^{[1
]}

D'Arcy-Evans, Nicholas ^{[1
]}

Koolmeister, Tobias ^{[1
]}

Henriksson, Martin ^{[1
]}

Michel, Dana ^{[15
]}

de Ory, Ana ^{[16
]}

Acero, Lucia ^{[8
]}

Calvete, Oriol ^{[17
]}

Scobie, Martin ^{[1
]}

Hertweck, Christian ^{[11
,18
]}

Vilotijevic, Ivan ^{[14
]}

Kalderen, Christina ^{[1
]}

机构：

[1] Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden

[2] Inst Invest Biomed Alberto Sols CSIC UAM, Madrid 28029, Spain

[3] Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain

[4] Univ Bath, Ctr Therapeut Innovat, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England

[5] Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden

[6] Norwegian Univ Sci & Technol, Dept Clin & Mol Med IKOM, N-7491 Trondheim, Norway

[7] SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway

[8] Hosp La Paz Inst Hlth Res IdiPAZ, Expt Therapies & Novel Biomarkers Canc, Madrid, Spain

[9] Uppsala Univ, Fac Med, Dept Med Biochem & Microbiol, Disciplinary Domain Med & Pharm, Uppsala, Sweden

[10] SINTEF Ocean, Dept Environm & New Resources, N-7496 Trondheim, Norway

[11] Leibniz Inst Nat Prod Res & Infect Biol, Hans Knoll Inst, Dept Biomol Chem, D-07745 Jena, Germany

[12] Lund Univ, Dept Expt Med Sci, Lund, Sweden

[13] Univ Sheffield, Sheffield Canc Ctr, Dept Oncol & Metab, Sheffield S10 2RX, S Yorkshire, England

[14] Friedrich Schiller Univ Jena, Inst Organ & Macromol Chem, D-07743 Jena, Germany

[15] Res Inst Sweden RISE, Unit Proc Chem 1, Chem Proc & Pharmaceut Dev, S-15136 Sodertalje, Sweden

[16] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden

[17] Spanish Natl Canc Res Ctr CNIO, Familial Canc Clin Unit, Human Canc Genet Programme, Madrid 28029, Spain

[18] Friedrich Schiller Univ Jena, Inst Microbiol, D-07743 Jena, Germany

[19] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain

[20] Goethe Univ Frankfurt, Inst Biochem 2, D-60590 Frankfurt, Germany

[21] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60590 Frankfurt, Germany

来源：

SCIENCE | 2022年 / 376卷 / 6600期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

8-OXOGUANINE; ASSAY; INHIBITORS; PRODUCT; DOMAIN;

D O I：

10.1126/science.abf8980

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta,delta-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.

引用

页码：1471 / +

页数：80

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