THE SCRIPPS RESEARCH INSTITUTE
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For infonnation:
Robin B. Goldsmith
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Embargoedby ScienceMasazine:
For wire servicesand broadcastnews,April 22, t993,3 p.m. PacificTime
F'or print media, April 23, 1993
Scripps ResearchersDevelop Insights into How Proteins RecognizeDNA and RNA
to Regulate Gene Expression
La Jolla, CA. April 21, t993 -- Scientistsat The ScrippsResearchInstitutehave
determinedfor the first time the way in which a single classof proteins can bind both to
DNA and RNA and, by so doing, have achieveda more profound understandingof the
processof generegulation. As reportedin this week's issueof the journal Science,they
have shownwhich of the nine tandemly-repeated
modules,or motifs, of a zinc finger
protein recognizeDNA and which recognizeRNA.
By better understandingthe recognitionprocess,scientistshave the potential for
controlling the expressionof genesat will, accordingto PeterE. Wright, Ph.D., and
Joel M. Gottesfeld,Ph.D., two of the study'sauthors,and chairmanand associate
member,respectively,of Scripps' Departmentof MolecularBiology. Their work
provides insights into how zinc finger proteinsmay function as a switch to turn on or off
the function of a gene.
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Scripps ResearchersDevelopInsights into How Proteins
RecognizeDNA and RNA to RegulateGene Expression
"Many diseasesarisefrom geneexpressiongonewrong; the wrong genesare
expressedat the wrong times, or they're not expressedat all, or they are expressedas
mutations. cancer, for example,is aberrantgeneexpression,"saidwright.
"What is particularlyexcitingaboutour insight into recognitionby this particular
protein, " accordingto Gottesfeld,"is that a protein of this type is involved in Wilms'
tumor, a rather rare but potentiallyfatal form of kidney cancergenerallyfound in
children under 14 yearsof age." He continued,"In theory, the long-termimplications
of the study could leadus towardthe developmentof inhibitorsor activatorsof specific
genesthat could turn on a tumor suppression
geneor turn off an oncogene.
"
The zinc finger proteinwas the first specificgeneregulatoryDNA binding
protein from a higher animalisolatedand cloned. What makesthis protein unique is its
ability not only to perform the generegulatoryfunction, but to bind the product of the
geneit regulates,or RNA. Its role in binding the geneis in turning the geneon. It
servesas a storageparticlefor RNA. This RNA is usedby the cell in the processof
protein synthesis.
The fundamentalunit of the protein is its so-calledzinc finger. This protein
consistsof nine of theseunits. Throuehthe methodof recombinantDNA. the TSRI
scientistshave found that the first threeunits are responsiblefor the recognitionof
DNA, and the next four for RNA. They havediscoveredthat the regionsof the protein
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Scripps ResearchersDevelopInsights into How proteins
RecognizeDNA and RNA to RegulateGene Expression
that give it specificityare different and perform thesedifferent functions. This was
achievedby removingdifferent regionsof the genefor the protein. Then, thesewere
expressedin bacteria,purified and testedfor whetherthey would bind DNA or RNA
using a specificassay.A painstakinglycareful quantitativeanalysiswas critical in
determining how well the units bound to RNA and DNA.
The protein's interactionwith DNA and RNA may ultimately leadto the design
of new molecules,potentiallynew therapeuticsthat can regulategenefunction. It may
be possibleto reconfigurethe units of the protein and bind them in different ways into
new combinationsthat do not exist in nature. By so doing, theseproteinsthen could
recognizedifferent genesand either activateor inhibit their functions.
Becauseof the work in this study, accordingto its authors,scientistshave
receivedthe first indicationthat different fingers can perform different functions. This,
in turn, will provide cluesand insightsinto other large, multi-finger proteins.
Additional authorsof the study in Science,which is titled, "MolecularBasisfor
SpecificRecognitionof Both RNA and DNA by a Zrnc Finger Protein," are TSRI
researchers
KarenR. Clemens,Ph.D., VeronicaJ. Wolf, StevenJ. McBryant,Penghua
Zbang,Ph.D., and Xiubel.Liao,Ph.D.
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