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Loophole in traffic laws challenges
current understanding of genetics
Yu and Karijolich studied pseudouridine, a slightly different version of the
RNA component uridine. The enzymes
that copy DNA to RNA and vice versa
can’t tell the difference
between the two components, but the subtle chemical tweak — akin to writing
a letter in a hard-to-read,
byzantine font — relays an
entirely different meaning to
the ribosome, the researchers suggest.
the mRNA, replacing the uridine in the
codon that signals a halt in protein production with pseudouridine. If pseudouridine behaved just like uridine, then
cells would prematurely stop production
of the detoxifying protein and wouldn’t
be able to grow in the presence of copper.
Yeast cells that replaced uridine in
the stop sign with pseudouridine could
grow on copper, the researchers report.
Looking more closely, the team found
that instead of reading the stop sign
as “stop,” ribosomes interpreted the
pseudouridine-containing
codon as an instruction to
insert one of the amino acids
serine, threonine, phenylalanine or tyrosine into the
protein.
And Yu and Karijolich’s technique
might be used to fix genetic errors, too.
Introducing stop sign–busting pseudo-
uridine into an RNA may one day help
people with rare genetic diseases in
which one of their genes contains an
early stop codon, Alfonzo says. s
codons by cellular machinery called
ribosomes. Ribosomes then convert the
mRNA instructions into proteins.
The team also created
a system that would
cause yeast cells to edit
“Misplacing a
pseudouridine
could make
things a
physiological
mess.”
juAN ALfoNzo
The result is “ground-
breaking,” says Nina Papavasiliou, a
molecular biologist at Rockefeller Uni-
versity in New York City. “It says that we
don’t fully understand how ribosomes
decode RNAs.”
That discovery could also mean that
genes contain more information than
scientists have previously realized,
Papavasiliou says.
That choice of amino acids
by the ribosome has biolo-
gists reeling, because those
aren’t even the amino acids
usually chosen when the protein facto-
ries do occasionally run stop signs.
“When you know the literature, you
would expect other” amino acids, says
Henri Grosjean, a biochemist and genet-
icist at the University of Paris–South.
Apparently ribosomes haven’t read
those papers.
Pseudouridine is already known to
be important for the function of many
types of RNA in cells. Yu and Karijolich
engineered a system
to discover whether
mRNAs containing the
modified letter might
also have a slightly different function than
those with plain old
uridine. The researchers created a flawed
copper-detoxifying gene
called CUP1 that contained a signal to stop
making protein early.
NH
Whether pseudouridine plays a part
in changing the genetic code in nature
remains to be seen, but researchers are
betting that it does. The implications
for health and disease could be great,
says Juan Alfonzo, a molecular biologist
at Ohio State University in Columbus.
Pseudouridines may be required to
make some proteins correctly, but “
misplacing a pseudouridine could make
things a physiological mess,” he says,
causing some proteins to have flaws,
even fatal ones.
C
OH
T. DUBÉ
By Tina Hesman Saey
Biology’s rules may be full of exceptions,
but a new discovery has uncovered a
violation in a rule so fundamental that
geneticists call it the central dogma.
The molecular equivalent of writing
one RNA letter in a different font can
change the way a cell’s protein-building
machinery interprets the genetic code,
Yitao Yu and John Karijolich of the University of Rochester in New York report
in the June 16 Nature. They found that
occasional conversions of a chemical component of RNA into a slightly
different form can cause a cell’s protein-building machinery to roll right
through a stop sign.
That might seem like a run-of-the-mill molecular traffic violation, but it
results in an entirely different protein
than the one encoded by the DNA — a
clear violation of the central dogma,
which holds that DNA is the repository
for all genetic instructions in a cell. The
tenet declares that those instructions are
carefully transcribed into multiple messenger RNA, or mRNA, copies, which are
then read in three-letter chunks called
Pseudouridine is a flipped-around, or isomerized, version
of the RNA component uridine. A carbon atom, instead
of a nitrogen, attaches pseudouracil to its sugar back-
bone. The change makes the RNA molecule stiffer.
O
H
O
H
N
N
C
O
O
O
N
O
OO
O
OH
O
Ribose sugar Pseudouracil
Uridine
Pseudouridine
