个人简介

Johns Hopkins University - Ph.D. (1986) University of Geneva, Switzerland - Postdoc. Fellow (1987) ETH, Switzerland - NSF Postdoc. Fellow (1988-1990) Fulbright Scholar, 2002

研究领域

Organic Chemistry/Chemical Biology

DNA and RNA encode genetic information in all modern organisms. In this process, DNA is transcribed into m-RNA, and m-RNA in turn is translated into protein. Nucleic acids are therefore central to life as we know it. Our laboratory seeks to define those molecular features of DNA and RNA that are essential for its function as a genetic material. Additional goals of this work include the creation of possible "missing links" in the evolution of modern nucleic acids from prebiotic reagents, and the engineering of nucleic acids that might serve as pharmaceutical or diagnostic agents. One project has examined the importance that the repeating negative charge found in the phosphodiester backbone of DNA has in determining its properties. The approach taken was to alter the charge density of DNA by appending positively charged ammonium ions to the nucleobases. This results in the charge neutralization of DNA by rendering it zwitterionic. DNA modified in this way is still able to recognize an unmodified complementary strand. One interesting consequence of introducing zwiterionic nucleotides into DNA is that they cause DNA double helices to bend. Other projects underway also examine non-standard nucleotide oligomers whose properties may be relevant to the origins of life on the primitive Earth, or may be useful in controlling gene expression at present. With respect to the former, RNA or RNA-like polymers are models for the first biotic, self-replicating molecules based on the following empirical observations: RNA participates in template-directed synthetic reactions in the absence of enzymes, and it catalyzes a variety of natural (and unnatural) reactions. One oligomer prepared recently in our laboratory replaces the standard 3',5'-internucleotide linkage with a non-standard 2',5'-linkage. We have found 2',5'-linked nucleic acids associate to form double-stranded and triple-stranded helices both with themselves and natural nucleic acids. We have also found 2',5'-linked nucleic acids serve as templates in the non-enzymatic transfer of genetic information. In the area of DNA with non-standard bases, we have uncovered of a DNA pentaplex (see figure) a DNA structure with five helical strands. Previously, the greatest number of strands found within a DNA helical complex was four.

近期论文

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Hashimoto, H.; Nelson, M.G.; Switzer, C. "Zwitterionic DNA," J. Am. Chem. Soc. 1993, 115, 7128-7134. Jung, K.-E.; Switzer, C. "2',5'-DNA Containing Guanine and Cytosine Forms Stable Duplexes," J. Am. Chem. Soc. 1994, 116, 6059-6061. Robinson, H.; Jung, K.-E.; Switzer, C.; Wang, A., H.-J. "DNA with 2'-5' Phospho-diester Bonds Forms a Duplex Structure in the A-Type Conformation," J. Am. Chem. Soc. 1995, 117, 837-838. Bandaru, R.; Hashimoto, H.; Switzer, C. "An Inverted Motif for Oligonucleotide Triplexes: Adenosine-Pseudouridine-Adenosine (A-?-A)," J. Org. Chem. 1995, 60, 786-787. Prakash, T. P.; Jung, K.-E.; Switzer, C. "RNA Recognition by the 2'-Structural Isomer of DNA," Chem. Comm. 1996, 1793-1794. Strauss, J. K.; Roberts, C.; Nelson, M.G.; Switzer, C.; Maher, L. J. "DNA Bending by Tethered Cations," Proc. Natl. Acad. Sci., U. S. A. 1996, 93, 9515-9520. Roberts, C.; Bandaru, R.; Switzer, C. "Theoretical and Experimental Study of iso-C and iso-G: Base-Pairing in an Expanded Genetic System." J. Am. Chem. Soc. 1997, 119, 4640-4649. Prakash, T. P.; Roberts, C.; Switzer, C. "Activity of 2',5'-Linked RNA in the Template-Directed Oligomerization of Mononucleotides," Angewandte Chemie, Int. Ed. Engl., 1997, 36, 1522-1523. Roberts, C.; Chaput, J.; Switzer, C. "Beyond G-quartets: Cation Induced Formation of Homogenous and Chimeric DNA Tetraplexes Incorporating iso-G and G," Chemistry and Biology 1997, 4, 899-908. Robinson, H.; Bauer, C.; Gao, Y.-G.; Roberts, C.; Switzer, C.; Wang, A. H.-J. "2'-Deoxy-Isoguanosine Adopts More Than One Tautomer to Base-Pair with Thymidine: Direct Observation by Crystallography," Biochemistry 1998, 37, 10897-10905. Green, R.; Switzer, C.; Noller, H. F. "Ribosome-Catalyzed Peptide Bond Formation with an A-Site Substrate Covalently Linked to 23S Ribosomal RNA," Science 1998, 280, 286-289. Chaput, J. C.; Switzer, C. "A DNA Pentaplex Incorporating Nucleobase Quintets," Proceedings of the National Academy of Sciences, U.S.A. 1999, 96, 10614-10619. Rice, K. P.; Chaput, J. C.; Cox, M. M.; Switzer, C. "RecA Protein Promotes Strand Exchange with DNA Substrates Containing Isoguanine and 5-Methyl Isocytosine" Biochemistry (2000) 39, 10177-10188. Chaput, J.C., Switzer, C. "Nonenzymatic oligomerization on templates containing phosphodiester-linked acyclic glycerol nucleic acid analogues ," J. Mol. Evol., (2000) 51, 464-470. Chaput JC, Switzer C. "Non-enzymatic transcription of an IsoG center dot IsoC base pair ," J. Am. Chem. Soc., (2000) 122, 12866-12867. Hardwidge PR, Lee DK, Prakash TP, Iglesias B, Den RB, Switzer C, Maher LJ. DNA bending by asymmetrically tethered cations: influence of tether flexibility. Chemistry and Biology (2001) 8, 967-980. Chaput, J. C., Sinha, S., Switzer, C. "5-Propynyluracil*diaminopurine: an efficient base-pair for non-enzymatic transcription of DNA," Chem. Comm., (2002) 1568-1569. Sinha, S., Kim, P. H., Switzer, C. "2',5'-Linked DNA is a template for polymerase-directed DNA synthesis," J. Am. Chem. Soc., (2004) 126, 40-41. Switzer, C., Sinha, S., Kim, P. H., Heuberger, B. H. "A Purine-Like Nickel(II) Base-Pair for DNA" Angewandte Chemie-International Edition, (2005) 44, 1529-1532. Switzer C, Shin D "A pyrimidine-like nickel(II) DNA base pair". Chem. Comm., (2005) 1342-1344.