The Decoding Code in mRNA 
Raymond F. Gesteland, Ph.D. — Investigator 
Dr. Gesteland is also Professor of Human Genetics at the University of Utah School of Medicine and 
Professor of Biology and Adjunct Professor of Bioengineering at the University of Utah. He received his B.S. 
degree in chemistry and his M.S. degree in biochemistry from the University of Wisconsin. He earned his 
Ph.D. degree in biochemistry from Harvard University, where he studied with J. D. Watson. Dr. Gesteland 
was an NIH postdoctoral fellow at the Institute de Biologie Moleculaire, Geneva, Switzerland. He served 
as Assistant Director and Investigator at Cold Spring Harbor Laboratory, New York, before assuming his 
present responsibilities. 
THE genetic code precisely specifies the iden- 
tification of each of the 20 amino acids from 
the set of 6 1 triplets in mRNA, with three triplets 
dedicated to termination. As a ribosome moves 
progressively along the mRNA deciphering it, the 
contiguous triplets contain all the information 
necessary to specify amino acid sequence. How- 
ever, there is another code, also encrypted by the 
linear order of bases in mRNA, that carries infor- 
mation about the mechanism of translation. 
This code specifies how the common genetic 
code should be implemented for each mRNA. In 
some cases the additional information may be 
quite simple, consisting of instructions that tell 
the ribosome where to start and where to stop 
decoding. In other cases this secondary code radi- 
cally changes the decoding process so that indi- 
vidual mRNAs use a different version of the ge- 
netic code, altered either in the meaning of 
certain codons or in the linear readout mecha- 
nism. This set of instructions could be called the 
"decoding code," in that it operates on the ge- 
netic code. Different decoding codes individual- 
ize mRNAs. 
A decoding code operating during the deci- 
phering of a specific mRNA often results in a vio- 
lation of the conventional genetic code. This can 
occur with a set frequency, so that the same 
mRNA produces two different protein products; 
but the frequency can also depend on metabolic 
state, thus providing another point at which gene 
expression is controlled. 
For example, the ribosomal machinery can be 
instructed to read a nontriplet number of bases at 
one site so that an alternate reading frame will be 
used from that point on. Or a proportion of the 
ribosomes can be instructed to jump from one 
site to another on the same mRNA so that noncon- 
tiguous codons will be read out. Or the meaning 
of specific codons can be altered so that a ribo- 
some reads a stop codon as an amino acid, or even 
as a new amino acid that is not a member of the 
conventional set of 20. Each of these unusual 
events is specified by the decoding code 
information. 
The diversity of schemes for encrypting infor- 
mation for the decoding code in individual 
mRNAs is just beginning to be appreciated. In 
some cases, rather simple sequences are in- 
volved; in others, sequence dictates complex 
RNA structures. 
The signals in mRNA that carry the instructions 
for programmed ribosomal frameshifting usually 
include a shift site where the frame changes and a 
stimulator sequence that greatly increases the 
shift site's efficiency. The shift site consists of 
4-7 nucleotides that allow a ribosomal-bound 
tRNA decoding in the first frame to slip forward 
or backward by one nucleotide to get into the 
new frame. The stimulator information can be 
upstream of the shift site, as in the case of the RF2 
gene in Escherichia coli, where 5-6 nucleotides 
need to pair directly with a specific sequence in 
ribosomal RNA in order to stimulate the shift. Or 
it can be downstream, as in the case of many retro- 
viruses and retroviral-like genes where the spe- 
cific interactions are less clear and the mRNA 
contains secondary and tertiary structures that 
somehow stimulate frameshifting at the upstream 
shift site. The combination of shift site and stimu- 
lator sequences constitutes the decoding code 
that tells how the standard genetic code should 
be corrupted for translation of a specific message. 
There is only one compelling case of ribosomal 
jumping, and here the decoding code is complex. 
The mRNA for gene 60 of bacteriophage T4 has a 
gap of 50 nucleotides that is very efficiently by- 
passed by ribosomes. The mRNA sequence ele- 
ments involved include both structural informa- 
tion in the gap and upstream information in the 
form of the amino acid sequence of the growing 
peptide chain that must interact with the same 
part of the complex. 
Other versions of the decoding code reprogram 
stop codons to specify amino acids. Some retrovi- 
ruses (e.g. , murine leukemia virus, MuLV) make a 
fusion protein from two in-frame genes separated 
by a UAG stop codon, which in this case is de- 
coded as glutamine. The decoding code that spe- 
cifies this includes a downstream element whose 
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