SirT1, the mammalian ortholog of yeast Sir2, regulates a variety of cellular processes in mammalian cells, such as cellular stress response and energy metabolism, contributing to possible anti-aging effects. On the other hand, SirT1 activity is also important for tumor cell growth and survival, possibly due to SirT1's anti- apoptotic effect. Therefore, SirT1 has important implications in both aging and cancer, making SirT1 activity a double-edged sword that requires tight regulation. However, the regulation of SirT1 is unclear. In order to understand the regulation of SirT1, we set out to identify SirT1-associated proteins. Through tandem affinity purification and mass spectrum analysis, we have identified deleted in breast cancer-1 (DBC1) as a SirT1- associated protein. The DBC1 gene localizes to a region (8p21) that is frequently deleted in breast cancers;and loss of DBC1 expression has been detected in some breast and lung cancer cell lines. However, the causal relationship between loss of DBC1 and tumorigenesis has not been established. The cellular functions of DBC1 protein are also unclear. Our preliminary results suggest that DBC1 directly interacts with SirT1 and inhibits SirT1 activity. Downregulation of DBC1 potentiates SirT1-dependent inhibition of apoptosis in response to DNA damage. In addition, loss of DBC1 promotes tumorigenesis in the presence of carcinogens. Based on these observations, we hypothesize that DBC1 negatively regulates SirT1, thereby affecting DNA damage response, aging and tumorigenesis. To build on our previous observations, we now propose the following specific aims: 1. Investigate SirT1-dependent and SirT1-independent function of DBC1. 2. Investigate the regulation of SirT1-DBC1 interaction following DNA damage. 3. Use DBC1 knockout mice to explore the physiological role of DBC1 in aging and tumorigenesis. Results from these studies will not only shed new light on the regulation of SirT1, but also provide important insight into the molecular mechanisms of aging and cancer.
The protein deacetylase SirT1 is linked to both aging and cancer. However, the regulation of SirT1 is unclear. We will investigate the regulation of SirT1 by DBC1, which will provide important insights into the molecular mechanism of aging and cancer.
|Deng, Min; Yang, Xu; Qin, Bo et al. (2016) Deubiquitination and Activation of AMPK by USP10. Mol Cell 61:614-24|
|Gao, Yayi; Tang, Jiayou; Chen, Weiqian et al. (2015) Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci U S A 112:E3246-54|
|Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71|
|Qin, Bo; Minter-Dykhouse, Katherine; Yu, Jia et al. (2015) DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep 10:1324-34|
|Lee, Seung Baek; Kim, Jung Jin; Nam, Hyun-Ja et al. (2015) Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1. Mol Cell 60:21-34|
|Lin, Yi-Hui; Yuan, Jian; Pei, Huadong et al. (2015) KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair. PLoS One 10:e0123935|
|Xu, Qiuran; Yang, Caihong; Du, Yu et al. (2014) AMPK regulates histone H2B O-GlcNAcylation. Nucleic Acids Res 42:5594-604|
|Liu, Tongzheng; Lin, Yi-Hui; Leng, Wenchuan et al. (2014) A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. Mol Cell 56:681-95|
|Qin, Bo; Gao, Bowen; Yu, Jia et al. (2013) Ataxia telangiectasia-mutated- and Rad3-related protein regulates the DNA damage-induced G2/M checkpoint through the Aurora A cofactor Bora protein. J Biol Chem 288:16139-44|
|Yuan, Jian; Luo, Kuntian; Liu, Tongzheng et al. (2012) Regulation of SIRT1 activity by genotoxic stress. Genes Dev 26:791-6|
Showing the most recent 10 out of 17 publications