Dynamic Processing of a Common Oxidative DNA Lesion by the First Two Enzymes of the Base Excision Repair Pathway |
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| Affiliation: | 1. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA;2. The Ohio State Biophysics Ph.D. Program, The Ohio State University, Columbus, OH 43210, USA;3. Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA;1. University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics, 12801 East 17th Avenue, Aurora, Colorado 80045, USA;2. Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Anderson University, Department of Chemistry and Biology, 316 Boulevard, Anderson, SC 29621, USA;1. Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA;2. Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA;3. Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA;4. The Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA;5. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;1. Institute for Biochemistry and Pathobiochemistry, Department of Systems Biology, Faculty of Medicine, Ruhr University of Bochum, 44780 Bochum, Germany;2. Munich Center for Integrated Protein Science at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany;3. Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany;4. Saarland University, 66421 Homburg, Germany;1. Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, United States;2. Department of Chemistry, Dartmouth College, Hanover, NH 03755, United States;3. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States;1. Laboratoire de Microbiologie et de Génétique Moléculaires, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France;2. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia;1. Groupe «Réparation de l''ADN», Equipe Labellisée par la Ligue Nationale Contre le Cancer, CNRS UMR8200, Université Paris-Sud, Université Paris-Saclay, Gustave Roussy Cancer Campus, F-94805 Villejuif Cedex, France;2. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland;3. Institute of Genetics and Biotechnology, University of Warsaw, Warsaw, Poland;4. Institute of Human Genetics, UMR 9002, CNRS - University of Montpellier, Replication and Genome Dynamics, 141 rue de la Cardonille, 34396, Montpellier, France;5. CNRS UMR8126, Université Paris-Sud, Université Paris-Saclay, Gustave Roussy Cancer Campus, F-94805 Villejuif Cedex, France;6. Department of Molecular Biology and Genetics, Faculty of Biology, al-Farabi Kazakh National University, 0530040, Almaty, Kazakhstan;7. Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk 630090, Russia;8. Novosibirsk State University, Novosibirsk 630090, Russia;9. National laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan |
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| Abstract: | Base excision repair (BER) is the primary pathway by which eukaryotic cells resolve single base damage. One common example of single base damage is 8-oxo-7,8-dihydro-2ʹ-deoxoguanine (8-oxoG). High incidence and mutagenic potential of 8-oxoG necessitate rapid and efficient DNA repair. How BER enzymes coordinate their activities to resolve 8-oxoG damage while limiting cytotoxic BER intermediates from propagating genomic instability remains unclear. Here we use single-molecule Förster resonance energy transfer (smFRET) and ensemble-level techniques to characterize the activities and interactions of consecutive BER enzymes important for repair of 8-oxoG. In addition to characterizing the damage searching and processing mechanisms of human 8-oxoguanine glycosylase 1 (hOGG1), our data support the existence of a ternary complex between hOGG1, the damaged DNA substrate, and human AP endonuclease 1 (APE1). Our results indicate that hOGG1 is actively displaced from its abasic site containing product by protein–protein interactions with APE1 to ensure timely repair of damaged DNA. |
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| Keywords: | Base excision repair Stopped-flow Single-molecule Förster resonance energy transfer Human 8-oxoguanine glycosylase Human AP endonuclease AP site" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" apurinic or apyrimidinic/abasic site BER" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" Base excision repair 8-oxoG" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" 8-oxo-7,8-dihydro-2ʹ-deoxoguanine smFRET" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" single-molecule Förster resonance energy transfer hOGG1" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" human 8-oxoguanine glycosylase 1 APE1" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" AP endonuclease 1 WT" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" wild-type |
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