Ribonuclease P and the Discovery of Catalytic RNA: the Work of Sidney Altman

Sidney Altman was born in Montreal in 1939. He attended the Massachusetts Institute of Technology where he studied physics. During his final semester at MIT, Altman took an introductory course in molecular biology, a subject that had begun to generate a great deal of excitement in the scientific community. In 1960 Altman graduated from MIT and worked for the next 2 years as a teaching assistant in the Department of Physics at Columbia University while he waited for a position to open up in a lab. Around this time, he decided to switch his focus from physics to molecular biology. In 1962 Altman left Columbia and enrolled as a graduate student in biophysics at the University of Colorado Medical Center. There he worked with Leonard S. Lerman, studying the effects of acridines on the replication of bacteriophage T4 DNA. He earned his Ph.D. in biophysics in 1967 and went to work briefly as a research assistant in molecular biology at Vanderbilt University. In 1967, he joined Mathew Meselson’s laboratory at Harvard University, continuing his research on the T4 bacteriophage. Two years later he became a member of the group led by Sydney Brenner and Francis Crick at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. Altman arrived at the MRC laboratory with the intention of studying the three-dimensional structure of tRNA using physical-chemical methods. However, upon his arrival, Brenner and Crick informed Altman that the crystal structure of yeast tRNA had recently been solved and that there was no need for the studies originally outlined for him. Altman instead proposed that he make acridine-induced mutants of tRNA from E. coli to determine if altering spatial relationships in tRNA, by deleting or adding a nucleotide to its sequence, would drastically alter the function of the molecule. His resulting mutants lacked the usual function of suppressor tRNAs and made no mature tRNA in vivo, but they reverted to wild type at a very high rate. This suggested that there might be an unstable duplication of the gene for tRNA, and Altman reasoned that if he could isolate the RNA transcript, he might be able to understand the nature of the duplication event. Altman succeeded in isolating the transcript of the gene for tRNA (1) and discovered that there were extra nucleotides at both ends of the mature molecule (2). When the precursor tRNA was mixed with an extract of E. coli, it was immediately apparent that enzymes in the cell extract could remove the “extra” nucleotides from both the 5 and 3 -ends of the mature tRNA sequence. The purification of an endonucleolytic ribonuclease from E. coli extract is the subject of the first Journal of Biological Chemistry (JBC) Classic reprinted here. Altman found that the purified enzyme cleaved a single phosphodiester bond in the tRNA precursor molecule, removing all the extra nucleotides present at the 5 -end of the precursor molecule. This was in contrast to what appeared to be non-specific exonucleolytic degradation at the 3 -end of the molecule. Altman named this new enzyme ribonuclease P (RNase P). THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 282, No. 7, Issue of February 16, p. e5, 2007 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A.