title: Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress.
abstract: Sirtuin 3 (Sirt3), a major mitochondrial NAD(+)-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metabolism, aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 physically associated with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degradation of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a critical role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We observed that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.
authors.affiliation: Department of Pharmacology, Milton S Hershey Medical Center, Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA. yxc24@psu.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.forename: A S P
authors.initials: AS
authors.lastname: Gowda
authors.forename: Y
authors.initials: Y
authors.lastname: Shan
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Y-S
authors.initials: YS
authors.lastname: Yuan
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: K
authors.initials: K
authors.lastname: Huber-Keener
authors.forename: J W
authors.initials: JW
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.forename: T E
authors.initials: TE
authors.lastname: Spratt
authors.forename: J-M
authors.initials: JM
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D018384:Oxidative Stress; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D002154:Calpain; C466093:SIRT3 protein, human; D056566:Sirtuin 3