1. Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells
- Author
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Renata Santos, Françoise Auchère, Nicole Boggetto, Caroline Brossas, Sophie D. Lefevre, Jean-Michel Camadro, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), French Government (CNRS), the French FA Patient Organization (AFAF) the Agence Nationale de la Recherche (ANR Maladies Rares, France), Funding to pay the Open Access publication charges for this article was provided by the French FA Patient Organization (AFAF)., Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm - Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Thermique de Lyon (CETHIL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)
- Subjects
DNA Repair ,[SDV]Life Sciences [q-bio] ,Gene Expression ,Apoptosis ,medicine.disease_cause ,Antioxidants ,AP endonuclease ,Gene Expression Regulation, Fungal ,Iron-Binding Proteins ,DNA Breaks, Double-Stranded ,Anaerobiosis ,DNA, Fungal ,Genetics (clinical) ,0303 health sciences ,030302 biochemistry & molecular biology ,Articles ,General Medicine ,Base excision repair ,DNA repair protein XRCC4 ,Oxidants ,Glutathione ,Oxidation-Reduction ,Alkylating Agents ,Saccharomyces cerevisiae Proteins ,DNA repair ,DNA damage ,Saccharomyces cerevisiae ,Biology ,DNA, Mitochondrial ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Endodeoxyribonucleases ,Microbial Viability ,Mutagenesis ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Cycle Checkpoints ,Hydrogen Peroxide ,Methyl Methanesulfonate ,Molecular biology ,Oxidative Stress ,DNA Repair Enzymes ,Friedreich Ataxia ,Frataxin ,biology.protein ,Reactive Oxygen Species ,Oxidative stress - Abstract
International audience; Frataxin deficiency results in mitochondrial dysfunction and oxidative stress and it is the cause of the hereditary neurodegenerative disease Friedreich ataxia (FA). Here, we present evidence that one of the pleiotropic effects of oxidative stress in frataxin-deficient yeast cells (Δyfh1 mutant) is damage to nuclear DNA and that repair requires the Apn1 AP-endonuclease of the base excision repair pathway. Major phenotypes of Δyfh1 cells are respiratory deficit, disturbed iron homeostasis and sensitivity to oxidants. These phenotypes are weak or absent under anaerobiosis. We show here that exposure of anaerobically grown Δyfh1 cells to oxygen leads to down-regulation of antioxidant defenses, increase in reactive oxygen species, delay in G1- and S-phases of the cell cycle and damage to mitochondrial and nuclear DNA. Nuclear DNA lesions in Δyfh1 cells are primarily caused by oxidized bases and single-strand breaks that can be detected 15-30 min after oxygen exposition. The Apn1 enzyme is essential for the repair of the DNA lesions in Δyfh1 cells. Compared with Δyfh1, the double Δyfh1Δapn1 mutant shows growth impairment, increased mutagenesis and extreme sensitivity to H(2)O(2). On the contrary, overexpression of the APN1 gene in Δyfh1 cells decreases spontaneous and induced mutagenesis. Our results show that frataxin deficiency in yeast cells leads to increased DNA base oxidation and requirement of Apn1 for repair, suggesting that DNA damage and repair could be important features in FA disease progression.
- Published
- 2012
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