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Sisyphean movement of motor
proteins may help preserve DNA integrity
Life Sciences Editor
photo to enlarge
by L. Brian Stauffer
Ha, a professor of physics, left, and his postdoctoral
fellow Sua Myong studied the Rep helicase from an
— Researchers studying how proteins called helicases travel along
strands of DNA have found that when the proteins hit an obstacle they
snap back to where they began, repeating the process over and over,
possibly playing a preventative role in keeping the genome intact.
Taekjip Ha, a professor of physics at the University of Illinois at
Urbana-Champaign and a Howard Hughes Medical Institute investigator,
likens the biological scenario to Boston Red Sox baseball; the team
rolls along only to hit a late-season obstacle called the New York Yankees.
Then, like the always-anticipated annual cry from Chicago Cubs fan,
it’s back to square one next year.
However, instead of causing more misery, as is the case for a baseball
fan, this motor protein’s starting over may serve a beneficial
purpose, clearing undesired proteins from the DNA, Ha said. The research
was done in vitro, using purified proteins and studied with a technique
that visualizes individual molecules on DNA. Whether the scenario plays
out in real cells in not known and under exploration.
photo to enlarge
courtesy Taekjip Ha
helicase (blue) moves rapidly on a highly flexible
DNA track. Such movement may prevent the accumulation
of toxic proteins on the DNA.
The discovery appears
in the Oct. 27 issue of the journal Nature, along with a separate “News
& Views” article by Eckhard Jankowsky, a biochemist at the
Center for RNA Molecular Biology in Case Western University’s
School of Medicine, who wrote about the potential importance of the
Ha’s postdoctoral fellow Sua Myong led the study, looking at the
Rep helicase from an E-coli bacterium. Rep is known to be involved in
restarting DNA replication stalled by DNA damage. As a single protein,
a monomer, Rep can travel one way along a single strand of DNA but by
itself cannot unzip it. Rep’s progress was visualized using the
single molecule fluorescence resonance energy transfer (FRET) technique
that Ha had developed.
By tagging the protein and DNA with green and red dyes, Myong measured
FRET changes as Rep traveled along single DNA strands, which are short
segments extending out from double strands. Each time the protein reached
either the junction of the full double-stranded DNA or hit an artificially
created protein obstacle, Rep instantly returned to near the beginning
of the single strand on which it had initially bound.
Upon closer examination using FRET, researchers discovered that Rep’s
configuration gradually closed as it reached the obstacle in its path.
Then, conformational changes of Rep allow it to grab and transfer to
the end of the single-stranded DNA, leading to the next cycle.
“Although the very flexible single strand of DNA likely bombards
the protein constantly, the protein doesn’t seem to pay attention
to this overture until it hits a physical blockade,” Ha said.
Researchers had theorized that obstacles would force motor proteins
to disengage from DNA. “The finding was totally unexpected and
may indicate a new function for the protein,” Ha said. Jankowsky
wrote that scientists “should not immediately search for the helix
that the enzyme unzips, but instead remember how Rep snaps back.”
In cells, single strands of DNA often occur when something is wrong,
Ha said. The recycling action, he said, may represent a desirable function
of the protein by keeping it engaged on a single strand, allowing time
for repairs that allow normal DNA replication.
The human body has more than 200 types of helicases involved in replication,
transcription, repair and other genetic processes, Ha said. Defective
helicases have been linked to increased cancer risks and premature aging.
Co-authors with Myong and Ha were Ivan Rasnik, a former postdoctoral
fellow who now is a professor of physics at Emory University in Atlanta;
Chirlmin Joo, a doctoral student in Ha’s lab; and Timothy M. Lohman,
a professor of biochemistry and molecular biophysics at the Washington
University School of Medicine in St. Louis.
The National Institutes of Health funded the research.