Nuclear genome instability, a hallmark of cancer, is thought to be an early event in tumorigenesis including malignancies induced from IR either from incidental exposure or secondary to therapy. It is well established that mammalian cells contain fidelity proteins that appear to protect against both endogenous and exogenous forms of genotoxic stress including ionizing radiation (IR)-induced genomic instability. This idea is based on one of the fundamental paradigms in biology: that is mammalian cells contain fidelity proteins that recognize specific conditions, including cell damage, and subsequently initiate signaling cascades that maintain cellular homeostatic poise. In addition, loss of function or genetic mutation of these fidelity proteins has been shown to create tumor permissive cellular phenotype suggesting that these proteins also function as tumors suppressors (TS). Preliminary data in our laboratory suggests that SIRT3, which is a genomically expressed, mitochondrial localized protein, is TS and cells lacking SIRT3 exhibit increased IR- induced genomic instability. Thus, the overarching goal of this proposal is to determine a mechanistic connection between SIRT3, mitochondrial metabolism, specifically superoxide levels, and IR genomic instability as well as IR-induced cancers. In this proposal we hypothesize that SIRT3 protects against IR-induced genomic instability and carcinogenesis via the regulation of MnSOD activity and the post translation modification of a reversible acetyl lysine. In addition, we are also proposing that lysine acetylation may be a primary posttranslational modification employed to regulate mitochondrial proteins. To investigate a mechanistic connection between SIRT3, MnSOD, and IR-induced genomic instability a series of in vitro and in vivo model systems will be used.
Nuclear genome instability, a hallmark of cancer, is thought to be an early event in tumorigenesis including malignancies induced from IR either from incidental exposure or secondary to therapy. In this proposal we suggest that the mitochondrial is an important target in IR-induced genomic instability and carcinogenesis.
|Traver, Geri; Mont, Stacey; Gius, David et al. (2017) Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 112:578-586|
|Zou, Xianghui; Zhu, Yueming; Park, Seong-Hoon et al. (2017) SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth. Cancer Res 77:3990-3999|
|Jablonski, Renea P; Kim, Seok-Jo; Cheresh, Paul et al. (2017) SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31:2520-2532|
|Yang, Xiaoyan; Park, Seong-Hoon; Chang, Hsiang-Chun et al. (2017) Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest 127:1505-1516|
|Song, Ha Yong; Biancucci, Marco; Kang, Hong-Jun et al. (2016) SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Oncotarget 7:80336-80349|
|Park, Seong-Hoon; Ozden, Ozkan; Liu, Guoxiang et al. (2016) SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth. Cancer Res 76:3802-12|
|Vidimar, Vania; Gius, David; Chakravarti, Debabrata et al. (2016) Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas. Sci Adv 2:e1601132|
|Zhang, Hui; Head, PamelaSara E; Daddacha, Waaqo et al. (2016) ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA. Cell Rep 14:1435-1447|
|Zou, Xianghui; Santa-Maria, Cesar Augusto; O'Brien, Joseph et al. (2016) Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype. Antioxid Redox Signal 25:326-36|
|Wang, Xiaoxin X; Edelstein, Michal Herman; Gafter, Uzi et al. (2016) G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. J Am Soc Nephrol 27:1362-78|
Showing the most recent 10 out of 34 publications