Abstract

Biochemical Society Transactions 26 Paoella, G., Sproat, B. and Lamond, A. I . (1992) EMBO J. 11, 1913-1919 27 Beigelman, L., McSwiggen, J. A., Draper, K. G., Gonzalez, C., Jensen, K., Karpeisky, A. M., Modak, A. S., Matulic-Adamic, J., DiRenzo, A. B., Haeberli, P., Tracz, D., Grimm, S., Wincott, F. E., Thackray, V. G. and Usman, N. (1995) J. Biol. Chem. 270, 28 Heidenreich, O., Benseler, F., Fahrenholz, A. and Eckstein, F. (1994) J. Biol. Chem. 269, 2131-2138 29 Thomson, J. B., Tuschl, T. and Eckstein, F. (1993) Nucleic Acids Res. 21, 5600-5603 30 Kiehntopf, M., Brach, M. A., Licht, T., Petschauer, S., Karawajew, L., Kirschning, C. and Herrmann, F. (1994) EMBO J. 13,4645-4652 31 Heidenreich, 0. and Eckstein, F. (1992) J. Biol. Chem. 267, 1904-1909 32 Herschlag, D. (1995) J. Biol. Chem. 270, 33 Heidenreich, O., Kang, S.-H., Brown, I). A., Xu, X., Swiderski, P., Rossi, J. J., Eckstein, F. and Nerenberg, M. (1995) Nucleic Acids Res. 23, 34 Romani, A. and Scarpa, A. (1992) Arch. Biochem. Biophys. 298, 1-12 35 Lyngstadaas, S. P., Risnes, S., Sproat, B. S., Thrane, P. S. and Prydz, H. P. (1995) EMBO J. 14, 36 Flory, C. M., Pavco, P. A., Jarvis, T. C., Lesch, M. E., Wincott, F. E., Beigelman, L., Hunt, 111, S. W. and Schrier, D. J. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 754-758 37 Eckstein, F. and Lilley, D. M. J. (eds.) (1996) Nucleic Acids and Molecular Biology, vol. 10, RNA Catalysis, Springer Verlag, Heidelberg 38 Christoffersen, R. E. and Marr, J. J. (1995) J. Med. Chem. 38,2023-2037 39 Sigurdsson, S. Th., Thomson, J. B. and Eckstein, F. (1996) in RNA Structure and Function (Simons, R. W. and Grunberg-Manago, M., eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, in the press Received 11 March 1996 Molecular palaeontology: understanding catalytic mechanisms in the RNA world by excavating clues from a ribozyme three-dimensional structure W. G. Scott Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, U.K. Ribozymes and the RNA world T h e discovery in the last decade that RNA can act as an enzyme refuted one of the main tenets of the so-called central dogma of molecular biology, i.e. that all enzymes must be proteins. T h e finding that RNA possesses catalytic activity, and in some cases can act as a true enzyme, has inspired research efforts dedicated not only to understanding the mechanisms of RNA-cata- lysed cleavage and ligation reactions [ 1,2], but also to developing ribozyme-based therapies tar- geted against RNA viruses and oncogene mRNA T h e discovery that RNA can be an enzyme also provides an escape from a paradox posed by the central dogma: if nucleic acids contain the heritable genetic information required for pro- tein synthesis, and if proteins are required for nucleic acid synthesis and replication, which evolved first? O n e possible answer is that RNA in principle can function both as a heritable infor- mation-encoding molecule and as an enzyme. Life therefore may have evolved from molecules, or assemblies of molecules, in a prebiotic ‘RNA Volume 24 world’ populated by self-replicating RNAs [4]. Indeed, the development of experimental tech- niques which allow in vitro selection and evolu- tion of RNA sequences possessing desired catalytic traits by screening randomized RNA libraries offers the exciting prospect of discover- ing RNAs that can replicate themselves effi- ciently [S]. Although such a discovery would not prove the existence of a prebiotic RNA world, it would clearly demonstrate that such a hypothesis of evolution is reasonable. Much of our understanding of the details of physicochemical mechanisms and function of protein enzymes is based upon our knowledge of the three-dimensional structures of these macro- molecules obtained by high-resolution tech- niques such as X-ray crystallography and NMR. In much the same way that three-dimensional structures of protein enzymes have been of para- mount importance for understanding classical enzymes, so too would the three-dimensional structures of RNA enzymes influence our under- standing of ribozyme catalysis, both in the cur- rent biological world and in a prebiotic RNA

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