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November 25, 1988, Vol 260, No. 20 >
ARTICLE | November 25, 1988

Ribozymes and Their Medical Implications FREE

Thomas R. Cech, PhD
[+] Author Affiliations

Based on a lecture given at the presentation of the Albert Lasker Basic Medical Research Award, New York, Nov 18,1988.

Reprints not available.


JAMA. 1988;260(20):3030-3034. doi:10.1001/jama.1988.03410200086031
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Published online
Article
References

Certain RNA molecules can mediate their own cleavage or splicing or act as enzymes to promote reactions on substrate RNA molecules. Thus, RNA is not restricted to being a passive carrier of genetic information but can have an active role in directing cellular biochemistry. These findings suggest the possibility that other cellular RNAs, including the RNA components of small nuclear ribonucleoproteins, of the ribosome, and of various ribonucleoprotein enzymes, are catalysts. RNA enzymes (ribozymes) can be used as sequence-specific RNA cleavage agents in vitro, providing useful tools for biochemical studies of RNA. On a more speculative note, ribozymes directed against viral RNAs have the potential of serving as therapeutic agents. Finally, some infectious agents, including hepatitis 8 virus and perhaps poliovirus and rhinoviruses, are themselves ribozymes, providing potential targets for pharmaceuticals.

(JAMA 1988;260:3030-3034)

REFERENCES

1 +
Berget SM, Moore C, Sharp PA:  Spliced segments at the 5' terminus of adenovirus 2 late mRNA . Proc Natl Acad Sci USA 1977;;74:3171-3175.
2 +
Chow LT, Gelinas RE, Broker TR, et al:  An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA . Cell 1977;;12:1-8.
3 +
Gilbert W:  Why genes in pieces? Nature 1978;;271:501.
4 +
Padgett RA, Grabowski PJ, Konarska MM, et al:  Splicing of messenger RNA precursors . Ann Rev Biochem 1986;;55:1119-1150.
5 +
Maniatis T, Reed R:  The role of small nuclear ribonucleoprotein particles in pre-mRNA splicing . Nature 1987;;325:673-678.
6 +
Cech TR, Zaug AJ, Grabowski PJ:  In vitro splicing of the ribosomal RNA precursor of Tetrahymena: Involvement of a guanosine nucleotide in the excision of the intervening sequence . Cell 1981;;27:487-496.
7 +
Kruger K, Grabowski PJ, Zaug AJ, et al:  Selfsplicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena . Cell 1982;;31:147-157.
8 +
Cech TR:  The generality of self-splicing RNA: Relationship to nuclear mRNA splicing . Cell 1986;;44:207-210.
9 +
Peebles CL, Perlman PS, Mecklenburg KL, et al:  A self-splicing RNA excises an intron lariat . Cell 1986;;44:213-223.
10 +
Van der Veen R, Arnberg AC, Van der Horst G, et al:  Excised group II introns in yeast mitochondria are lariats and can be formed by self-splicing in vitro . Cell 1986;;44:225-234.
11 +
Lazowska J, Jacq C, Slonimski PP:  Sequence of introns and flanking exons in wild type and box3 mutants of cytochrome b reveals an interlaced splicing protein coded by an intron . Cell 1980;;22:333-348.
12 +
Akins RA, Lambowitz AM:  A protein required for splicing group I introns in Neurospora mitochondria is mitochondrial tyrosyl-tRNA synthetase or a derivative thereof . Cell 1987;;50:331-345.
13 +
Gampel A, Tzagoloff A:  In vitro splicing of the terminal intervening sequence of Saccharomyces cerevisiae cytochrome b pre-mRNA . Mol Cell Biol 1987;;7:2545-2551.
14 +
Greer CL, Leebles CL, Gegenheimer P, et al:  Mechanism of action of a yeast RNA ligase in tRNA splicing . Cell 1983;;32:537-546.
15 +
Zaug AJ, Cech TR:  The intervening sequence excised from the ribosomal RNA precursor of Tetrahymena contains a 5′-terminal guanosine residue not encoded by the DNA . Nucleic Acids Res 1982;;10:2823-2838.
16 +
Zaug AJ, Grabowski PJ, Cech TR:  Autocatalytic cyclization of an excised intervening sequence is a cleavage-ligation reaction . Nature 1983;;301:578-583.
17 +
Bass BL, Cech TR:  Specific interaction between the self-splicing RNA of Tetrahymena and its guanosine substrate: Implications for biological catalysis by RNA . Nature 1984;;308:820-826.
18 +
Davies RW, Waring RB, Ray JA, et al:  Making ends meet: A model for RNA splicing in fungal mitochondria . Nature 1982;;300:719-724.
19 +
Waring RB, Towner P, Minter SJ, et al:  Splicesite selection by a self-splicing RNA of Tetrahymena . Nature 1986;;321:133-139.
20 +
Been MD, Cech TR:  One binding site determines sequence specificity of Tetrahymena prerRNA self-splicing, trans-splicing, and RNA enzyme activity . Cell 1986;;47:207-216.
21 +
Tanner NK, Cech TR:  Guanosine binding required for cyclization of the self-splicing intervening sequence ribonucleic acid from Tetrahymena thermophila . Biochemistry 1987;;26:3330-3340.
22 +
Kay PS, Inoue T:  Catalysis of splicing-related reactions between dinucleotides by a ribozyme . Nature 1987;;327:343-346.
23 +
Zaug AJ, Kent JR, Cech TR:  A labile phosphodiester bond at the ligation junction in a circular intervening sequence . Science 1984;;224:574-578.
24 +
Michel F, Dujon B:  Conservation of RNA secondary structures in two intron families including mitochondrial-, chloroplast-, and nuclear-encoded members . EMBO J 1983;;2:33-38.
25 +
Zaug AJ, Cech TR:  The intervening sequence RNA of Tetrahymena is an enzyme . Science 1986;;231:470-475.
26 +
Sharp PA:  On the origin of RNA splicing and introns . Cell 1985;;42:397-400.
27 +
Darnell JE, Doolittle WF:  Speculations on the early course of evolution . Proc Natl Acad Sci USA 1986;;83:1271-1275.
28 +
Cech TR:  A model for the RNA-catalyzed replication of RNA . Proc Natl Acad Sci USA 1986;;83:4360-4363.
29 +
Weiner AM:  The origins of life , in Watson JD, Hopkins NH, Roberts JW, et al (eds): Molecular Biology of the Gene , ed 4. Melno Park, Calif, Benjamin/Cummings Publishing Co Inc, 1987;, vol 2, pp 1098-1163.
30 +
Zaug AJ, Been MD, Cech TR:  The Tetrahymena ribozyme acts like an RNA restriction endonuclease . Nature 1986;;324:429-433.
31 +
Guerrier-Takada C, Gardiner K, Marsh T, et al:  The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme . Cell 1983;;35:849-857.
32 +
Wong TW, Clayton DA:  DNA primase of human mitochondria is associated with structural RNA that is essential for enzymatic activity . Cell 1986;;45:817-825.
33 +
Chang DD, Clayton DA:  A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA . Science 1987;;235:1178-1184.
34 +
Greider CW, Blackburn EH:  The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity . Cell 1987;;51:887-898.
35 +
Prody GA, Bakos JT, Buzayan JM, et al:  Autolytic processing of dimeric plant virus satellite RNA . Science 1986;;231:1577-1580.
36 +
Hutchins CJ, Rathjen PD, Forster AC, et al:  Self-cleavage of plus and minus RNA transcripts of avocado sunblotch viroid . Nucleic Acids Res 1986;;14:3627-3640.
37 +
Uhlenbeck OC:  A small catalytic oligoribonucleotide . Nature 1987;;328:596-600.
38 +
Forster AC, Symons RH:  Self-cleavage of virusoid RNA is performed by the proposed 55-nucleotide active site . Cell 1987;;50:9-16.
39 +
Epstein LM, Gall JG:  Self-cleaving transcripts of satellite DNA from the newt . Cell 1987;;48:535-543.
40 +
Haseloff J, Gerlach WL:  Simple RNA enzymes with new and highly specific endoribonuclease activities . Nature 1988;;334:585-591.
41 +
Wang K-S, Choo Q-L, Weiner AJ, et al:  Structure, sequence and expression of the hepatitis delta (8) viral genome . Nature 1986;;323:508-514.
42 +
Kos A, Dijkema R, Arnberg AC, et al:  The hepatitis (8) virus possesses a circular RNA . Nature 1986;;323:558-560.
43 +
Chen P-J, Kalpana G, Goldberg J, et al:  Structure and replication of the genome of the hepatitis δ virus . Proc Natl Acad Sci USA 1986;;83:8774-8778.
44 +
Sharmeen L, Kuo MYP, Dinter-Gottlieb G, et al:  Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage . J Virol 1988;;62:2674-2679.
45 +
Liebman M, Rubin J, Sundaralingam M:  Nonintercalative binding of ethidium bromide to nucleic acids: Crystal structure of an ethidium-tRNA molecular complex . Proc Natl Acad Sci USA 1977;;74:4821-4825.
46 +
Tanner NK, Cech TR:  Self-catalyzed cyclization of the intervening sequence RNA of Tetrahymena: Inhibition by methidiumpropyl-EDTA and localization of the major dye binding sites . Nucleic Acids Res 1985;;13:7759-7779.
47 +
Flanegan JB, Pettersson RF, Ambros V, et al:  Covalent linkage of a protein to a defined nucleotide sequence at the 5' terminus of the virion and replicative intermediate RNAs of poliovirus . Proc Natl Acad Sci USA 1977;;74:961-965.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Berget SM, Moore C, Sharp PA:  Spliced segments at the 5' terminus of adenovirus 2 late mRNA . Proc Natl Acad Sci USA 1977;;74:3171-3175.
2 +
Chow LT, Gelinas RE, Broker TR, et al:  An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA . Cell 1977;;12:1-8.
3 +
Gilbert W:  Why genes in pieces? Nature 1978;;271:501.
4 +
Padgett RA, Grabowski PJ, Konarska MM, et al:  Splicing of messenger RNA precursors . Ann Rev Biochem 1986;;55:1119-1150.
5 +
Maniatis T, Reed R:  The role of small nuclear ribonucleoprotein particles in pre-mRNA splicing . Nature 1987;;325:673-678.
6 +
Cech TR, Zaug AJ, Grabowski PJ:  In vitro splicing of the ribosomal RNA precursor of Tetrahymena: Involvement of a guanosine nucleotide in the excision of the intervening sequence . Cell 1981;;27:487-496.
7 +
Kruger K, Grabowski PJ, Zaug AJ, et al:  Selfsplicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena . Cell 1982;;31:147-157.
8 +
Cech TR:  The generality of self-splicing RNA: Relationship to nuclear mRNA splicing . Cell 1986;;44:207-210.
9 +
Peebles CL, Perlman PS, Mecklenburg KL, et al:  A self-splicing RNA excises an intron lariat . Cell 1986;;44:213-223.
10 +
Van der Veen R, Arnberg AC, Van der Horst G, et al:  Excised group II introns in yeast mitochondria are lariats and can be formed by self-splicing in vitro . Cell 1986;;44:225-234.
11 +
Lazowska J, Jacq C, Slonimski PP:  Sequence of introns and flanking exons in wild type and box3 mutants of cytochrome b reveals an interlaced splicing protein coded by an intron . Cell 1980;;22:333-348.
12 +
Akins RA, Lambowitz AM:  A protein required for splicing group I introns in Neurospora mitochondria is mitochondrial tyrosyl-tRNA synthetase or a derivative thereof . Cell 1987;;50:331-345.
13 +
Gampel A, Tzagoloff A:  In vitro splicing of the terminal intervening sequence of Saccharomyces cerevisiae cytochrome b pre-mRNA . Mol Cell Biol 1987;;7:2545-2551.
14 +
Greer CL, Leebles CL, Gegenheimer P, et al:  Mechanism of action of a yeast RNA ligase in tRNA splicing . Cell 1983;;32:537-546.
15 +
Zaug AJ, Cech TR:  The intervening sequence excised from the ribosomal RNA precursor of Tetrahymena contains a 5′-terminal guanosine residue not encoded by the DNA . Nucleic Acids Res 1982;;10:2823-2838.
16 +
Zaug AJ, Grabowski PJ, Cech TR:  Autocatalytic cyclization of an excised intervening sequence is a cleavage-ligation reaction . Nature 1983;;301:578-583.
17 +
Bass BL, Cech TR:  Specific interaction between the self-splicing RNA of Tetrahymena and its guanosine substrate: Implications for biological catalysis by RNA . Nature 1984;;308:820-826.
18 +
Davies RW, Waring RB, Ray JA, et al:  Making ends meet: A model for RNA splicing in fungal mitochondria . Nature 1982;;300:719-724.
19 +
Waring RB, Towner P, Minter SJ, et al:  Splicesite selection by a self-splicing RNA of Tetrahymena . Nature 1986;;321:133-139.
20 +
Been MD, Cech TR:  One binding site determines sequence specificity of Tetrahymena prerRNA self-splicing, trans-splicing, and RNA enzyme activity . Cell 1986;;47:207-216.
21 +
Tanner NK, Cech TR:  Guanosine binding required for cyclization of the self-splicing intervening sequence ribonucleic acid from Tetrahymena thermophila . Biochemistry 1987;;26:3330-3340.
22 +
Kay PS, Inoue T:  Catalysis of splicing-related reactions between dinucleotides by a ribozyme . Nature 1987;;327:343-346.
23 +
Zaug AJ, Kent JR, Cech TR:  A labile phosphodiester bond at the ligation junction in a circular intervening sequence . Science 1984;;224:574-578.
24 +
Michel F, Dujon B:  Conservation of RNA secondary structures in two intron families including mitochondrial-, chloroplast-, and nuclear-encoded members . EMBO J 1983;;2:33-38.
25 +
Zaug AJ, Cech TR:  The intervening sequence RNA of Tetrahymena is an enzyme . Science 1986;;231:470-475.
26 +
Sharp PA:  On the origin of RNA splicing and introns . Cell 1985;;42:397-400.
27 +
Darnell JE, Doolittle WF:  Speculations on the early course of evolution . Proc Natl Acad Sci USA 1986;;83:1271-1275.
28 +
Cech TR:  A model for the RNA-catalyzed replication of RNA . Proc Natl Acad Sci USA 1986;;83:4360-4363.
29 +
Weiner AM:  The origins of life , in Watson JD, Hopkins NH, Roberts JW, et al (eds): Molecular Biology of the Gene , ed 4. Melno Park, Calif, Benjamin/Cummings Publishing Co Inc, 1987;, vol 2, pp 1098-1163.
30 +
Zaug AJ, Been MD, Cech TR:  The Tetrahymena ribozyme acts like an RNA restriction endonuclease . Nature 1986;;324:429-433.
31 +
Guerrier-Takada C, Gardiner K, Marsh T, et al:  The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme . Cell 1983;;35:849-857.
32 +
Wong TW, Clayton DA:  DNA primase of human mitochondria is associated with structural RNA that is essential for enzymatic activity . Cell 1986;;45:817-825.
33 +
Chang DD, Clayton DA:  A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA . Science 1987;;235:1178-1184.
34 +
Greider CW, Blackburn EH:  The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity . Cell 1987;;51:887-898.
35 +
Prody GA, Bakos JT, Buzayan JM, et al:  Autolytic processing of dimeric plant virus satellite RNA . Science 1986;;231:1577-1580.
36 +
Hutchins CJ, Rathjen PD, Forster AC, et al:  Self-cleavage of plus and minus RNA transcripts of avocado sunblotch viroid . Nucleic Acids Res 1986;;14:3627-3640.
37 +
Uhlenbeck OC:  A small catalytic oligoribonucleotide . Nature 1987;;328:596-600.
38 +
Forster AC, Symons RH:  Self-cleavage of virusoid RNA is performed by the proposed 55-nucleotide active site . Cell 1987;;50:9-16.
39 +
Epstein LM, Gall JG:  Self-cleaving transcripts of satellite DNA from the newt . Cell 1987;;48:535-543.
40 +
Haseloff J, Gerlach WL:  Simple RNA enzymes with new and highly specific endoribonuclease activities . Nature 1988;;334:585-591.
41 +
Wang K-S, Choo Q-L, Weiner AJ, et al:  Structure, sequence and expression of the hepatitis delta (8) viral genome . Nature 1986;;323:508-514.
42 +
Kos A, Dijkema R, Arnberg AC, et al:  The hepatitis (8) virus possesses a circular RNA . Nature 1986;;323:558-560.
43 +
Chen P-J, Kalpana G, Goldberg J, et al:  Structure and replication of the genome of the hepatitis δ virus . Proc Natl Acad Sci USA 1986;;83:8774-8778.
44 +
Sharmeen L, Kuo MYP, Dinter-Gottlieb G, et al:  Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage . J Virol 1988;;62:2674-2679.
45 +
Liebman M, Rubin J, Sundaralingam M:  Nonintercalative binding of ethidium bromide to nucleic acids: Crystal structure of an ethidium-tRNA molecular complex . Proc Natl Acad Sci USA 1977;;74:4821-4825.
46 +
Tanner NK, Cech TR:  Self-catalyzed cyclization of the intervening sequence RNA of Tetrahymena: Inhibition by methidiumpropyl-EDTA and localization of the major dye binding sites . Nucleic Acids Res 1985;;13:7759-7779.
47 +
Flanegan JB, Pettersson RF, Ambros V, et al:  Covalent linkage of a protein to a defined nucleotide sequence at the 5' terminus of the virion and replicative intermediate RNAs of poliovirus . Proc Natl Acad Sci USA 1977;;74:961-965.

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