Yi Wang, Ph.D.
Department of Biochemistry and Molecular Biology
Department of Molecular and Cellular Biology
Education and Awards
- Ph.D., Chemistry, 1992, Kansas State University
- Postdoctoral, Biochemistry, 1994-1996, The Rockefeller University
- Postdoctoral, Biochemistry and Molecular Biology, 1996-1998, NIH/NIDDK
DNA damage response (DDR) is crucial for maintaining genomic integrity and preventing cancer by coordinating the activation of checkpoints, repair of damaged DNA and activation of apoptosis. The goals of our research are to understand the molecular mechanism of DDR, to investigate how their deregulation leads to genome instability and cancer, and to identify new molecular targets for better treatment of cancer.
At the core of DDR are the two checkpoint kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM-Rad3-related), which are activated by DNA damage and phosphorylate wide range of substrates to initiate the signaling cascade. Thus, identification and characterization of in vivo ATM/ATR substrates hold the keys for the understanding of DDR. Using a mass spectrometry-based proteomic screen, we have identified hundreds of potential ATM/ATR substrates that represent many pathways not previously known in DDR. Notably, checkpoint assays suggest that proteins involved in ubiquitin-proteasome system (UPS) are required in mammalian DNA damage checkpoint control, thus revealing protein ubiquitination as an important regulatory mechanism downstream of ATM/ATR activation. We are validating a subset of the substrates to establish their functional links to DDR and genome stability.
One of the newly identified substrates is a previously uncharacterized protein RING finger and WD repeat domain 3 (RFWD3). The RFWD3 protein contains a RING finger domain, which is a conserved E3 ubiquitin (Ub) ligase domain, and a coiled-coil domain and a WD40 domain that mediate protein-protein interactions. We have shown that RFWD3 can form a complex with MDM2 and p53, and is required for the maintenance of high levels of p53 upon DNA damage induction. In vitro reactions demonstrate that RFWD3 exhibits robust E3 Ub ligase activity towards p53. Currently, we are using an integrated approach that combines genetics manipulation, proteomics and functional analysis to identify additional E3 ubquitination substrates of RFWD3 and uncover other biological processes that RFWD3 regulates.
- Shi Y, Chan DW, Jung SY, Malovannaya A, Wang Y, Qin J. A data set of human endogenous protein ubiquitination sites. Mol Cell Proteomics. 2011 May;10(5):M110.002089.
- Fu X, Yucer N, Liu S, Li M, Yi P, Mu JJ, Yang T, Chu J, Jung SY, O'Malley BW, Gu W, Qin J, Wang Y. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4579-84.
- Kim BJ, Li Y, Zhang J, Xi Y, Li Y, Yang T, Jung SY, Pan X, Chen R, Li W, Wang Y, Qin J. Genome-wide reinforcement of cohesin binding at pre-existing cohesin sites in response to ionizing radiation in human cells. J Biol Chem. 2010 Jul 23;285(30):22784-92.
- Malovannaya A, Li Y, Bulynko Y, Jung SY, Wang Y, Lanz RB, O'Malley BW, Qin J. Streamlined analysis schema for high-throughput identification of endogenous protein complexes. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2431-6
- Chan DW, Wang Y, Wu M, Wong J, Qin J, Zhao Y. Unbiased proteomic screen for binding proteins to modified lysines on histone H3. Proteomics. 2009 May;9(9):2343-54.
- Leng M, Bessuso D, Jung SY, Wang Y, Qin J. Targeting Plk1 to chromosome arms and regulating chromosome compaction by the PICH ATPase. Cell Cycle. 2008 May 15;7(10):1480-9.
- Luo H, Li Y, Mu JJ, Zhang J, Tonaka T, Hamamori Y, Jung SY, Wang Y, Qin J. Regulation of intra-S phase checkpoint by ionizing radiation (IR)-dependent and IR-independent phosphorylation of SMC3. J Biol Chem. 2008 Jul 11;283(28):19176-83.
- Zhang J, Shi X, Li Y, Kim BJ, Jia J, Huang Z, Yang T, Fu X, Jung SY, Wang Y, Zhang P, Kim ST, Pan X, Qin J. Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Mol Cell. 2008 Jul 11;31(1):143-51.
- Mu JJ, Wang Y, Luo H, Leng M, Zhang J, Yang T, Besusso D, Jung SY, Qin J. A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J Biol Chem. 2007 Jun 15;282(24):17330-4.
- Leng M, Chan DW, Luo H, Zhu C, Qin J, Wang Y. MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11485-90.