HOW A MOLECULAR SUPERMAN PROTECTS GENOME FROM DAMAGE
How many times have we
seen Superman swoop down from the heavens and rescue a would-be victim from a
rapidly oncoming train?
It's a familiar
scenario, played out hundreds of times in the movies. But the dramatic scene is
reenacted in real life every time a cell divides. In order for division to
occur, our genetic material must be faithfully replicated by a highly
complicated machine, whose parts are tiny enough to navigate among the strands
of the double helix.
The problem is that
our DNA is constantly in use, with other molecular machines continually
plucking at its strands to gain access to critical genes. In this other
process, known as transcription, the letters of our DNA are being copied to
form a template that will guide the formation of proteins. But these two
copying machines can't occupy the same bit of genetic track at once. Inevitably
they will collide -- unless a molecular Superman can remove the transcription
machinery and save the day.
Cold Spring Harbor
Laboratory (CSHL) scientists have found that this molecular Superman exists in
the form of a protein known as Dicer. Better known for its role in selectively
silencing genes via a process called RNA interference (RNAi), Dicer is now
understood to help free transcription machinery from DNA so that replication
can occur.
The team, led by
Robert Martienssen, a CSHL Professor and Howard Hughes Medical Institute
Investigator, concludes that this previously unknown function of Dicer is
critical to preserve the integrity of the genome in yeast. They point out that
collisions between the replication and transcription machinery lead to massive
changes across the genome -- changes that are associated with aging and
diseases like cancer.
Martienssen and his
colleagues previously found that RNAi resolves the conflict between
transcription and DNA replication in isolated areas of the genome where genes
are being silenced. "When Dicer is mutated, replication stalls and DNA in
the region becomes damaged," explains Martienssen. "This was a new
role for a protein that we thought functioned solely in RNAi."
In work published
today in Cell, Martienssen and his team explored if and how Dicer
might function more broadly, across the entire genome. The team, including lead
authors Stephane Castel, Ph.D., a graduate of the CSHL Watson School of
Biological Sciences, and Jie Ren, Ph.D., a postdoctoral researcher, found that
Dicer participates in the release of transcription machinery throughout the
genome. "Dicer's function isn't restricted to silenced genes,"
explains Ren. In fact, it controls the release at hundreds of extremely active
genes.
"These are genes
that are in constant use by the cell -- we call many of them 'housekeeping'
genes because they are required for basic survival," says Castel. At any
given time, transcription machinery can be found near these genes. Without the
help of Dicer, this machinery is headed for an almost certain collision when
replication occurs.
Are these collisions
really so catastrophic for the cell? The team found that the accidents cause
massive segments of DNA to be lost with each cell division. "These
chromosome rearrangements, known as genomic instability, are involved in aging
and cancer," says Ren. Other groups have shown that mutations in Dicer are
similarly associated with an increased risk of tumor formation. The team's
discovery may help to explain these observations, according to Martienssen.
"It may be that Dicer's role in cancer is to protect the genome by
preventing collisions between transcription and replication."
Comments
Post a Comment