Overall goal of my laboratory is to understand structure-function relationship of nucleic acids, which primarily adopt non-canonical structures. We are interested in learning the role of such structures in regulation of fundamental cellular processes, and utilize such molecules for therapeutic purposes.
We are particularly interested in studying a structural form known as G-quadruplex that both DNA and RNA sequences rich in guanosine residues can adopt. We intend to learn how the DNA G-quadruplexes regulate transcription and how the RNA G-quardruplexes can control translation. We will utilize biochemical and biophysical along with molecular biology and cell biology techniques to achieve these objectives.
DNA G-Quadruplexes in regulation of transcription: Relationship to diabetes and cancer
Recent studies from several labs have shown wide spread occurrence of G-rich sequences within the human genome. One particular G-rich area of interest is Insulin Linked Polymorphic Region (ILPR), located upstream of insulin gene. The ILPR region has been linked to juvenile or type I diabetes. The ILPR is unique among G-rich areas in the genome because of the unusual heterogeneity in the sequence. The most well studied G-rich area is the telomeric sequences found at the end of chromosomes. However, the telomeric regions consist of monotonic repetition of identical G-rich units. In contrast the ILPR is known to harbor more than a dozen different G-rich repeats. As such it presents a unique opportunity to study the structural polymorphism associated with G-quadruplex structures. The goal is to understand how such polymorphism influences the replication of this section in the genome and transcription of insulin.
Additionally, we are interested in studying other G-rich sequences found in the promoter region of various genes, especially growth factor genes and proto-oncogenes, with the broad long-term goal of understanding the fundamental structure-function relationship of DNA G-quadruplexes in regulating transcription.
RNA G-Quadruplexes in translation control and their role in cancer:
Bioinformatics analyses have discovered prevalence of G-rich sequences in regulatory regions of mRNA. The 5'-untranslated region (5'-UTR) is known to control translation of mRNA. Recently, we and others have shown that G-rich sequences present in the 5'-UTR can form G-quadruplex structures and repress translation. We are investigating in detail the role of such G-rich sequences in regulating translation of mRNA. We are particularly interested in understanding the roles played by such structures in regulating translation of mRNA from cancer related genes.
Scholarly, Creative & Professional Activities
"Coexistence of an ILPR i-motif and a partially folded structure with comparable mechanical stability revealed at the single molecular level," Dhakal, S., Schonhoft, J., Koirala, D., Yu, Z., Basu, S., and Mao, H.* (2010), J. Am. Chem. Soc., 132, 8991-8997.
"Prussian blue nanoparticles for cellular imaging: Towards a new generation of T1-weighted MRI contrast agents," Shokouhimehr, M., Soehnlen, E.S., Hao, J., Griswold, M., Flask, C., Fan, X., Basilion, J.P.*, Basu, S.*, and Huang, S.D. (2010), J. of Materials Chem., DOI: 10.1039/b923184f.
"Biocompatible Prussian blue nanoparticles: Preparation, stability, cytotoxicity, and potential use as an MRI contrast agent," Shokouhimehr, M., Soehnlen, E.S., Khitrin, A., Basu, S.*, and Huang, S.D.* (2010), Inorganic Chem. Comm., 13, 58-61.
"ILPR repeats adopt diverse G-quadruplex conformations that determine insulin binding," Schonhoft, J.D., Das, A., Achamyeleh, F., Samdani, S., Sewell, A., Mao, H., and Basu, S.* (2010), Biopolymers, 93, 21-31.
"An unusually stable G-quadruplex within 5'-UTR of the MT3 matrix metalloproteinase mRNA represses translation in eukaryotic cells", Morris, M.J. and Basu, S.* (2009), Biochemistry, 48, 5313-5319.
"Direct Experimental Evidence for Quadruplex-Quadruplex Interaction within the Human ILPR", Schonhoft, J. D., Bajracharya, R., Dhakal, S., Yu, Z., Mao, H.* and Basu, S.*,.(2009), Nucleic Acids Res. 37, 3310-3320.
"ILPR G-Quadruplexes Formed in Seconds Demonstrate High Mechanical Stabilities" Yu, Z., Schonhoft, J. D, Dhakal, S., Bajracharya, R., Hegde, R., Basu, S.*, and Mao, H*, (2009), J. Am. Chem. Soc., 131, 1876-1882.
"Intravesical antisense therapy for cystitis using TAT-peptide nucleic acid conjugates". Tyagi, P., Banerjee, R., Basu, S., Yoshimura, N., Chancellor, M., and Huang, L., (2006), Molecular Pharmaceutics,3, 398-406.
"Direct detection of specific monovalent metal ion binding to a DNA G-quartet by Tl-205 NMR". Basu, S., Szewczak, A., Cocco, M., and Strobel, S. A., (2000), J. Am. Chem. Soc., 122, 3240-3241.
"Thiophilic metal ion rescue of phosphorothioate interference within the Tetrahymena ribozyme P4-P6 domain," Basu, S., and Strobel, S. A., (1999), RNA, 5, 1399-1407.
"A specific monovalent metal ion integral to the A-A platform of the RNA tetraloop receptor." Basu, S., Rambo, R. P., Cate, J. H., Ferré-D´Amarre, A. R., Strobel, S. A. and Doudna, J. A., (1998), Nat. Struct. Biol., 5, 986-992.
"The Role of Recombinant DNA Technology in Medicinal Chemistry and Drug Discovery," Basu, S., and Oyelere, A., (2010), Burger's Medicinal Chemistry,(in press), D. Abraham (Ed.), John-Wiley.
"Analysis of the Ribozyme Structure/Function by Nucleotide Analog Interference Mapping (NAIM)," Basu, S., Pazsint, C. and Chowdhury, G., (2004), Methods in Molecular Biology: Catalytic Nucleic Acid Protocols, M. Sioud (Ed.), Humana Press.
Ph.D., Kimmel Cancer Center, Thomas Jefferson University, Post-doctoral Fellow, Yale University