Department of Molecular Medicine
 

Hai Rao, Ph.D. Hai  RaoPh.D.

Associate 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

  1. Baek GH, Cheng H, Kim I, and Rao H: (2012) The cdc48 and its cofactor vms1 are involved in cdc13 protein degradation. J Biol Chem. 287(32): 26788-95.
  2. Liu C, van Dyk D, Choe V, Yan J, Majumder S, Costanzo M, Bao B, Boone C, Huo K, Winey M, Fisk H, Andrews B, and Rao H: (2011) Ubiquitin ligase Ufd2 is required for efficient degradation of Mps1 kinase. J Biol Chem. 286(51): 43660-7.
  3. Baek GH, Kim I, and Rao H: (2011) The Cdc48 ATPase modulates the interaction between two proteolytic factors Ufd2 and Rad23. Proc Natl Acad Sci USA. 108(33): 13558-63.
  4. Yan J, Di Y, Shi H, Rao H, and Huo K: (2010) Overexpression of SCYL1-BP1 stabilizes functional p53 suppressing MDM2-mediated ubiquitination. FEBS Lett. 584(20): 4319-24.
  5. Yan J, Zhang D, Di Y, Shi H, Rao H, and Huo K: (2010) A newly identified Pirh2 substrate SCYL1-BP1 can bind to MDM2 and accelerate MDM2 self-ubiquitination. FEBS Lett. 584(15): 3275-8.
  6. Liu C, Choe V, and Rao H: (2010) Genome-wide approaches to systematically identify substrates of the ubiquitin-proteasome pathway. Trends Biotechnol. 28(9): 461-7.
  7. Hosomi A, Tanabe K, Hirayama H, Kim I, Rao H, and Suzuki T: (2010) Identification of an Htm1 (EDEM)-dependent, Mns1-independent Endoplasmic Reticulum-associated Degradation (ERAD) pathway in Saccharomyces cerevisiae: application of a novel assay for glycoproteiN ERAD. J Biol Chem. 285(32): 24324-34.
  8. Liu C, van Dyk D, Xu P, Choe V, Pan H, Peng J, Andrews B, and Rao H: (2010) Ubiquitin chain elongation enzyme Ufd2 regulates a subset of Doa10 substrates. J Biol Chem. 285(14): 10265-72.
  9. Li Y, Yan J, Kim I, Liu C, Huo K, and Rao H: (2010) Rad4 regulates protein turnover at a postubiquitylation step. Mol Biol Cell. 21(1): 177-85.
  10. Kim I, Li Y, Muniz P, and Rao H: (2009) Usa1 protein facilitates substrate ubiquitylation through two separate domains. PLos One. 4(10): e7604.
  11. Liu C, van Dyk D, Li Y, Andrews B, and Rao H: (2009) A genome-wide synthetic dosage lethality screen reveals multiple pathways that require the functioning of ubiquitin-binding proteins Rad23 and Dsk2. BMC Biol. 7: 75.
  12. Liu C, Apodaca J, Davis LE, and Rao H: (2007) Proteasome inhibition in wild-type yeast Saccharomyces cerevisiae cells. Biotechniques. 42(2): 158, 160, 162.
  13. Apodaca J, Kim I, and Rao H: (2006) Cellular tolerance of prion protein PrP in yeast involves proteolysis and the unfolded protein response. Biochem Biophys Res Commun. 347(1): 319-26.
  14. Kim I and Rao H: (2006) What's Ub chain linkage got to do with it? Sci STKE. 2006(330): pe 18.
  15. Kim I, Ahn J, Liu C, Tanabe K, Apodaca J, Suzuki T, and Rao H: (2006) The Png1-Rad23 complex regulates glycoprotein turnover. J Cell Biol. 172(2): 211-9.
  16. Apodaca J, Ahn J, Kim I, and Rao H: (2005) Analysis of ubiquitin chain-binding proteins by two-hybrid methods. Methods Enzymol. 399: 157-64.
  17. Kim I, Mi K, and Rao H: (2004) Multiple interactions of rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol Biol Cell. 15(7): 3357-65.
  18. Rao H and Sastry A: (2002) Recognition of specific ubiquitin conjugates is important for the proteolytic functions of the ubiquitin-associated domain proteins Dsk2 and Rad23. J Biol Chem. 277(14): 11691-5.
  19. Rao H, Uhlmann F, Nasmyth, K, and Varshavsky A: (2001) Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability. Nature. 410(6831): 955-9.