Department of Pharmacology, Milton S Hershey Medical Center, Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
Cell Death Dis. 2013 Jul 18;4(7):e731. doi: 10.1038/cddis.2013.254.
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.
Sirtuin 3（Sirt3）是一种主要的依赖 NAD（+）的线粒体去乙酰化酶，其靶向各种线粒体蛋白进行赖氨酸去乙酰化，调节重要的细胞功能，如能量代谢、衰老和应激反应。在这项研究中，我们鉴定了人类 8-氧鸟嘌呤-DNA 糖基化酶 1（OGG1），一种从受损基因组中切除 7,8-二氢-8-氧鸟嘌呤（8-oxoG）的 DNA 修复酶，为 Sirt3 的新靶标蛋白。我们发现 Sirt3 与 OGG1 物理结合，并使该 DNA 糖苷酶去乙酰化，Sirt3 的去乙酰化可防止 OGG1 蛋白的降解并控制其切割活性。我们进一步表明，Sirt3 通过调节 OGG1 的乙酰化和周转率在修复线粒体 DNA（mtDNA）损伤、保护线粒体完整性和防止氧化应激诱导的细胞凋亡中发挥关键作用。我们观察到，在电离辐射后，沉默 Sirt3 表达的人类肿瘤细胞表现出 mtDNA 氧化损伤的恶化，这可以通过 8-oxoG 和 4977 常见缺失的积累来衡量，并且与未沉默 Sirt3 表达的细胞相比，表现出更严重的线粒体功能障碍和更大的细胞凋亡。这里报道的结果不仅揭示了 Sirt3 在防御线粒体基因组免受氧化损伤和保护免受遗传毒性应激诱导的细胞凋亡方面的新功能和机制，还为支持新的 mtDNA 修复途径提供了证据。
