Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress

Y Cheng; X Ren; A S P Gowda; Y Shan; L Zhang; Y-S Yuan; R Patel; H Wu; K Huber-Keener; J W Yang; D Liu; T E Spratt; J-M Yang

doi:10.1038/cddis.2013.254

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Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress

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Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress

Y Cheng, X Ren, A S P Gowda, Y Shan, L Zhang, Y-S Yuan, R Patel, H Wu, K Huber-Keener, J W Yang, …

Cell death & disease, Vol.4(7), pp.e731-e731

07/18/2013

DOI: 10.1038/cddis.2013.254

PMCID: PMC3730425

PMID: 23868064

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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.

Apoptosis

DNA Repair

Oxidative Stress

Sirtuin 3 - genetics

Calpain - metabolism

Cell Proliferation

Sirtuin 3 - metabolism

Humans

Gene Knockdown Techniques

Protein Interaction Mapping

DNA, Mitochondrial - genetics

Proteolysis

HEK293 Cells

Membrane Potential, Mitochondrial

Cell Line, Tumor

Protein Binding

Protein Processing, Post-Translational

Acetylation

DNA Damage

DNA Glycosylases - metabolism

Details

Title: Subtitle: Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
Creators: Y Cheng - 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
X Ren
A S P Gowda
Y Shan
L Zhang - Pennsylvania State University
Y-S Yuan
R Patel
H Wu
K Huber-Keener
J W Yang
D Liu
T E Spratt
J-M Yang
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.4(7), pp.e731-e731
DOI: 10.1038/cddis.2013.254
PMID: 23868064
PMCID: PMC3730425
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Publisher: England
Grant note: R01 CA135038 / NCI NIH HHS R01CA135038 / NCI NIH HHS
Language: English
Date published: 07/18/2013
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9983931813602771

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