Hai
Rao,
Ph.D.
Assistant Professor
Profile and Contact Information |
Research
| Laboratory
RESEARCH
Research Program
Controlled proteolysis of a key regulator in any given biological process provides an important means for achieving its spatial gradients and allows for rapid adjustments of its concentration. Many proteins involved in cancer development and progression, including p53, cyclins, IkB, are degraded by the proteasome. Proteins that are targeted to the proteasome are first modified by ubiquitin (Ub), a highly conserved 76-residue polypeptide. Ubiquitylation - the covalent conjugation of Ub to target proteins - controls many basic cellular processes, including signal transduction, DNA repair, apoptosis, and transcription. Not surprisingly, defects in the Ub-proteasome system can lead to diseases ranging from cancer to neurodegenerative disorders. The recent discovery that BRCA1, a protein involved in breast cancer, functions as a key component in the Ub-mediated proteolytic pathway further emphasizes that studies of the Ub/proteasome system are essential for delineating the pathogenesis of various human diseases. The encouraging effect of proteasome inhibitors in treating cancer patients also begs for better understanding of the mechanisms and function of the Ub/proteasome system.
Our long-term goal is to understand how the fate of proteins is regulated by the ubiquitin (Ub) system. Specifically, we wish to understand how proteins modified by Ub are degraded by the proteasome. It is proposed that adaptor molecules, which selectively recognize ubiquitylated substrates, facilitate the proteolysis of substrates. We focus on S. cerevisiae Rad23-like proteins, Rad23, Dsk2, and Ddi1 that are candidate adaptor molecules involved in delivering ubiquitylated substrates to the proteasome. Another interest of the laboratory is the function of the Ub/proteasome system in protein quality control, which plays an important role in the aging process.
Selected Publications
- Rao, H., Uhlmann, F., Nasmyth, K., and Varshavsky, A. Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability. Nature 410: 955-959, 2001.
- Rao, H. and Sastry, A. Recognition of specific ubiquitin conjugates is important for the proteolytic functions of the UBA domain proteins Dsk2 and Rad23. J. Biol. Chem. 277: 11691-11695, 2002.
- Kim, I., Mi, K., and Rao, H. Multiple interactions of Rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Molec. Biol. Cell 15: 3357-3365, 2004.
- Apodaca, J., Ahn, J.M., Kim, I., and Rao, H. (2005) Analysis of Ub-binding proteins by yeast two-hybrid. Methods Enzymol. (in press).
- Kim, I., Ahn, J., Liu, C., Tanabe, K., Apodaca, J., Suzuki, T., and Rao, H. (2005) The Png1-Rad23 complex regulates glycoprotein turnover. (Submitted).