Shyamal D. Desai , PhD
Assistant Professor, PhD,
University of Bombay, 1991

Biography:
Dr. Desai obtained her Bachelor of Science and Master of Science in Biochemistry from University of Bombay in 1981 and 1983 respectively.  She received her Doctorate in Biochemistry from the University of Bombay in 1991. From 1991 to 1996, Dr. Desai did a post-doctoral fellowship at the UMDNJ-Robert Wood Johnson Medical School in New Jersey. Since 1996, she was a faculty member in the Department of Pharmacology at the UMDNJ/RWJMS.  During her tenure there she made a novel finding that ISG15 (a UBL) is overexpressed in many tumor cells and its overexpression interferes with protein polyubiquitination and degradation.  She also worked on the repair of topoisomerase I (TOP1)-mediated DNA damage.  She showed that one of the repair mechanisms for TOP1-DNA covalent complexes is through the activation of the ubiquitin/26S proteasome pathway.  This novel repair mechanism is quite significant and may have implications in the resistance mechanism to the clinically used TOP1-directed anticancer drugs (e.g. Toptecan). In 2007, Dr. Desai joined the LSUHSC as Assistant Professor in the Department of Biochemistry &Molecular Biology.

Research Interests:
• The roles of ubiquitin and ubiquitin-like proteins in cancer.
* Mechanism of tumor cell death and drug resistance.
* The roles of ubiquitin and ubiquitin-like protein ISG15 in neurodegenerative diseases.

The long-term goals of my research are
1) To understand the role of ubiquitin and ubiquitin-like protein ISG15 (Interferon-Stimulated Gene Factor 15) in tumorigenesis.
2) To understand the mechanism of tumor cell death and drug resistance. 3) Tounderstand the role of ubiquitin and ubiquitin-like protein ISG15 in neurodegenerative diseases.

Ubiquitin and ubiquitin-like proteins in tumorigenesis
ISG15 is an ubiquitin-like protein implicated in regulation of protein degradation.  However, the precise role of ISG15 in protein degradation is not known.  We have recently demonstrated that ISG15 is highly elevated and extensively conjugated to the cellular proteins in many tumors and tumor cell lines.  In addition, the elevated ISG15p interferes with the ubiquitin/26S proteasome pathway in tumor cells.

Aberrant protein degradation, which contributes to the elevated expression of key regulatory proteins e.g. cell cycle regulators, has been demonstrated to be important for tumorigenesis.  Our goal is, therefore, to understand if the elevated expression of ISG15 is responsible for the stabilization of these key regulatory proteins contributing to tumorigenesis.                                                
                         
Mechanism of tumor cell death and drug resistance.
The camptothecin (CPT) class of anticancer drugs (e.g. topotecan and irinotecan) is directed towards topoisomerase I (TOP1), a nuclear enzyme required for various DNA functions such as DNA replication and transcription.  Camptothecin converts TOP1 into a “poison” by stabilizing its covalent reaction intermediate, the “cleavable complex”.  Camptothecin selectively kills S-phase cells by a mechanism involving the collision between the moving replication fork and the cleavable complex.  Upon collision with the replication fork, the reversible TOP1 cleavable complexes are transformed into potentially lethal double-strand DNA breaks, causing cell cytotoxicity.  
                                                                       
TOP1-mediated DNA damage represents a unique form of DNA lesion.  The repair of TOP1-mediated DNA damage requires the removal of the covalently bound TOP1 and subsequent DNA repair. Recently, we have shown that TOP1 is rapidly multiubiquitinated and then degraded by the 26S proteasome in cells treated with CPT.  In addition, we have shown that many tumor cells are defective in ubiquitination and degradation of TOP1.  Together, these results could suggest that CPT-induced down-regulation of TOP1 occurs in normal cells but is impaired to a different and variable degree in tumor cells. 

It is unclear whether this difference between normal and tumor cells could contribute to the antitumor activity of CPT.  However, we have demonstrated that tumor cells defective in degradation of TOP1 are hypersensitive to CPT.  In addition, the elevated expression of ISG15 is responsible for the defective degradation of TOP1 and contributes to CPT cytotoxicity.  The possibility that ISG15 could be used as a tumor biomarker for the drug sensitivity in clinic is being investigated.
 
The role of ubiquitin and ubiquitin-like protein ISG15 in neurodegenerative diseases.
Ataxia Telangiectasia (A-T) (Boder-Sedgwick/Louis-Bar syndrome) is an inherited immunodeficiency disorder with a prevalence of 1 in 30,000-100,000 births.  A-T patients are characterized by pronounced facial spider veins (telangiectsia), recurrent sinopulmonory infections, and an irregular gate (ataxia), which results from progressive neuronal dysfunctions. These clinical presentations, secondary to the sensitivity to ionizing radiation and a marked predisposition to cancer, were explicated in 1995 by Savitsky et al. as an autosomal recessive mutation in the Ataxia Telangiectasia (ATM) gene. ATM is a 370 kDa nuclear Ser/Thr kinase contributing to the regulation of p53, BRCA1, and Chk2 signaling pathways, amongst others, and thus required for progression through mitotic checkpoints, double strand DNA repair, telomere repair, apoptosis, and meiosis. The central role of ATM in cell regulation suggests that loss of function mutations in ATM gene should result in broad pleiotropic effects.  Indeed, A-T patients suffer from growth retardation, a high incidence of cancer, and neuronal degeneration in the cerebellum leading to ataxia.   

The reason for the progressive neurodegeneration in AT patients is unclear.  However, non-degraded proteins have been found to accumulate in the post-mortem brains of people with inherited neurodegenerative diseases, such as Parkinson, Alzheimer and Huntington disease.  Enrichment of non-degraded proteins in neurons is suspected to contribute to the pathology of the disease.  Defects in the ubiquitin-26S proteasome pathway are responsible for the accumulation of non-degraded ubiquitinated proteins.  Interestingly, we have recently observed that targeted proteasome-mediated degradation is impaired in A-T cells. The reduced protein turnover in A-T cells is associated with elevated expression of ISG15. We therefore plan to test if the elevated expression of ISG15 in A-T is responsible for the defective protein turnover of the ubiquitinated proteins in brain and consequently leads to neurodegeneration in AT patients.

Selected Publications

Lin CP, Ban Y, Lyu YL, Desai SD, Liu LF. A ubiquitin-proteasome pathway for the repair of Top1-DNA covalent complexes. J Biol Chem. May 30 2008.

Desai, S. D, Wood, L. J.,  Tsai, Y. C.,  Hsieh, T. S.,  Marks, J. R.,  Scott, G. L.,  Giovanella, B. C., and Liu, L. F. ISG15 as a Novel Tumor Biomarker for Drug Sensitivity.  In Press, 2008

Desai, S. D., Haas, A. L., Wood, L. M., Tsai, Y, C., Pestka, S., Rubin, E. H., Saleem, A., Kamal, A. N., and Liu, L. F. Elevated expression of ISG15 in tumor cells inhibits protein degradation by 26S Proteasome. Cancer Res., 66: 921-8, 2006.

Desai, S. D., Li, T. K., Rodriguez-Bauman, A., Rubin, E. H., and Liu, L. F. Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res., 61: 5926-5932, 2001.

Mao, Y., Sun, M., Desai, S. D., and Liu, L. F. SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage. Proc. Natl. Acad. Sci. U.S.A, 97: 4046-4051, 2000.

Mao, Y., Desai, S. D., and Liu, L. F. SUMO-1 conjugation to human DNA topoisomerase II isozymes. J. Biol. Chem., 275: 26066-26073, 2000.
 
Desai, S. D., Liu, L. F., Vazquez-Abad, D., and D'Arpa, P. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J. Biol. Chem., 272: 24159-24164, 1997.