matic attachment of phosphate. An enzyme that 
phosphorylates RNA polymerase has been purified. 
One of the components of this enzyme is a protein 
that has previously been implicated in controlling 
the cell division cycle. This result may lead to a 
greater understanding of the genetic control of cell 
growth and the role RNA polymerase plays in this 
process. 
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 regula- 
tory systems known. The research of Investigator 
Susan Lindquist, Ph.D. (The University of Chicago) 
and her colleagues focuses on three aspects of the 
response. First, the rapid and reproducible induc- 
tion of new proteins is under study as a general 
model system to investigate mechanisms of genetic 
regulation in higher organisms. The group has 
shown that the major heat-shock protein, hsp70, is 
repressed during recovery from heat shock by a 
mechanism that recognizes the 3' end of the hsp70 
messenger RNA and targets it for degradation. Sec- 
ond, the laboratory is examining the mechanisms 
that cells employ to protect themselves from heat 
stress. They have found that one of the heat-shock 
proteins, hsp83, is essential for all temperatures 
but is especially required at higher concentrations 
for cell growth at higher temperatures. They have 
also found that a third protein, hspl06, is required 
for cells to tolerate short-term exposure to extreme 
temperatures without dying. Finally, the laboratory 
is interested in some practical applications of the 
heat-shock response. They have used the heat- 
shock promoter and translation signals to express 
the site-specific recombination system of the yeast 
2|jL plasmid in Drosophila. The induction of the 
recombinase by heat shock induces site-specific re- 
combination at recombination target sequences 
embedded in the Drosophila genome. This system 
should enhance methods of genetic analysis in Dro- 
sophila and is also likely to be applicable to other 
organisms. 
The laboratory of Investigator Joan Argetsinger 
Steitz, Ph.D. (Yale University) is continuing to inves- 
tigate how a number of recently discovered small 
particles contribute to basic cellular processes. 
These particles contain RNA and protein and play 
essential roles in the multiple steps by which infor- 
mation in the cell's DNA is expressed in the form of 
proteins. For instance, several of these particles are 
involved in RNA splicing, whereby nonsense seg- 
ments are removed from the RNA copies of genes, 
converting them to functional messengers. Impor- 
tant tools used to study these small particles are an- 
tibodies made by some patients with such rheu- 
matic diseases as systemic lupus erythematosus. 
Understanding the nature of the particles is there- 
fore important not only for basic molecular biology 
but also for improving the diagnosis and treatment 
of rheumatic disease. 
The diversity of unusual translation events that 
ribosomes display continues to occupy a major por- 
tion of the efforts of the laboratory of Investigator 
Raymond F. Gesteland, Ph.D. (University of Utah). 
Most retroviruses couple the synthesis of the GAG 
protein to the gag-pol precursor for the polymerase 
through the occasional sUpping by ribosomes into 
one of the alternative reading frames at special se- 
quences at the gag-pol junction. Fortunately these 
special sequences also cause bacterial ribosomes to 
make the same change in the reading frame follow- 
ing the same rules, and this provides an opportu- 
nity to work out the details of the reaction and to 
screen drugs efficiently for those that alter ribo- 
somal frameshifting. Rules for ribosome jumping 
are more complicated. The large jump that ribo- 
somes use to navigate past 50 nucleotides of un- 
translated mRNA during expression of the bacterio- 
phage T4 gene 60 requires a long stretch of 
upstream information. Surprisingly this turns out 
to be the peptide sequence of the growing chain 
that somehow interacts with the ribosome to tell it 
to jump. Study of these unusual events continues 
to reveal more secrets of the complicated ribosomal 
machinery of the cell. 
The major project under way in the laboratory of 
Assistant Investigator George M. Church, Ph.D. 
(Harvard Medical School) is directed at facilitating 
the sequencing of small genomes to compare them 
for conserved elements. To accomplish this rapidly 
and accurately, new sequencing tools have been de- 
veloped. One of these, multiplex sequencing, is a 
way of keeping a large set of DNA fragments as a 
precise mixture throughout most of the steps of se- 
quencing. Machines and software have been devel- 
oped that integrate automatic base assignment rou- 
tines with high-resolution image display and 
interactive multisequence alignments. Images with 
overlapping data can be easily retrieved to facilitate 
building and checking the final consensus se- 
quences. The technology is being applied in Dr. 
Church's laboratory to the sequencing of two bac- 
terial genomes, Escherichia coli and Salmonella 
typhimurium. 
Continued 
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