much deeper knowledge of structures in natural 
RNA molecules is required. 
Chemical reactions necessary for life are typically 
catalyzed by large molecules called enzymes. These 
are usually proteins, but in some cases ribonucleic 
acid (RNA), a form of genetic material, acts as an 
enzyme. The detailed folding of the RNA chain that 
allows it to act as a catalyst has been a subject of 
much interest. In the past year the laboratory of In- 
vestigator Thomas R. Cech, Ph.D. (University of Col- 
orado) converted one of the substrates bound by an 
RNA enzyme to an "explosive device." By identify- 
ing points of destruction of the RNA caused by this 
reagent, information about the three-dimensional 
structure of the active site was obtained. It has been 
thought that RNA enzymes catalyze an extremely 
limited repertoire of reactions. In the past year this 
group discovered that an RNA enzyme could cata- 
lyze a new class of reactions involving amino acids, 
the building blocks of proteins, rather than nucleo- 
tides, the building blocks of nucleic acids. 
Investigator Joan A. Steitz, Ph.D. (Yale University) 
and her colleagues are investigating how a number 
of small particles found in all cells contribute to 
basic life processes. These particles contain RNA 
and protein, and play essential roles in the multiple 
steps by which the information in the cell's DNA is 
expressed in the form of proteins. For instance, sev- 
eral of these particles are involved in RNA splicing 
whereby nonsense segments are removed from the 
RNA copies of genes, converting them to functional 
messengers. Important tools used to study these 
small particles are antibodies made by some patients 
with rheumatic diseases, like systemic lupus erythe- 
matosus. Understanding the nature of the particles is 
therefore important not only to basic molecular biol- 
ogy but also for improving the diagnosis and treat- 
ment of rheumatic disease. 
When cells of all types are exposed to environ- 
mental stress, such as mildly elevated temperatures, 
they respond by producing a small number of pro- 
teins called the heat-shock proteins. This response is 
one of the most highly conserved genetic regulatory 
systems known. The research of Investigator Susan L. 
Lindquist, Ph.D. (University of Chicago) and her col- 
leagues focuses on two aspects of the response. 
First, the laboratory is investigating the specific mo- 
lecular functions of the heat-shock proteins and has 
found that hsp82 is required for the formation of 
functional steroid receptors and plays an important 
role in activating the oncogenic protein pp60'''*'^''. 
On the other hand, hspI04 is required for cells to 
tolerate short-term exposure to extreme tempera- 
tures and other forms of stress without dying. This 
highly conserved protein contains two nucleotide- 
binding sites, both of which are required for stress 
tolerance. Genetic experiments demonstrate that 
the protein is related in function to hsp70, another 
highly conserved protein. Second, the rapid and re- 
producible induction of new proteins provides a 
general model system to investigate mechanisms of 
genetic regulation in higher organisms. This year 
the group has examined a new mechanism for regu- 
lating hsp70, by sequestration. This was first discov- 
ered when tissue culture cells were forced to ex- 
press the protein in the absence of stress. In normal 
Drosophila the mechanism operates in early em- 
bryos, where excess hsp70 expression may interfere 
with normal growth. 
Recent studies indicate that in the living cell 
there are specialized proteins called chaperones 
that help newly made proteins adjust from unfolded 
forms into characteristic biologically active three- 
dimensional structures. The laboratory of Associate 
Investigator Arthur L. Horwich, M.D. (Yale Univer- 
sity) originally discovered that heat-shock protein 
60 is a chaperone inside mitochondria. The 14 
hsp60 molecules comprise two stacked rings or a 
double-donut structure with which unfolded pro- 
teins become associated. In the presence of ATP and 
a second single-ring structure, proteins fold into the 
active forms and are released. During this past year 
the group has uncovered a new class of double-ring 
structures that also appear to be mediators of pro- 
tein folding. One member was found in thermo- 
philic archaebacteria, organisms that grow at tem- 
peratures near that of boiling water, and a second, 
related structure was detected in the cytoplasm of 
cells of higher organisms. 
The laboratory of Associate Investigator Jeffry L. 
Corden, Ph.D. (Johns Hopkins University) has dis- 
covered an unusual extension or "tail" on RNA poly- 
merase II, the enzyme that carries out the first step 
in expression of genetic information. The tail is a 
site of modification by enzymes that respond to sig- 
nals sent from outside the cell. How these signals 
modify the tail and how these modifications affect 
gene expression are the focus of current experi- 
ments. The results of these studies should allow for a 
better understanding of the regulation of gene ex- 
pression in normal processes such as growth and 
development and in abnormal situations such as 
cancer and birth defects. 
The research of Investigator Maynard V. Olson, 
Ph.D. (Washington University) involves interrelated 
studies of yeast and human DNA. Because yeast and 
human cells have similar genetic and biochemical 
properties, information gained by studying yeast is 
GENETICS 147 
