Study Finds Direction of Enzymes
Affects
DNA Repair
DNA repair enzymes do a much better job
of repairing damaged genes if they are facing in one direction instead of
the other. This and other details of how DNA repair is performed are
reported today in the online version of the journal Proceedings of
the National Academy of Sciences by researchers at Washington
State University and the National Institute of Environmental Health
Sciences.
According to the report, the repair
enzymes "distinguish" between various positions and may be two
to three times as effective, depending on whether the damage to be
repaired is facing "toward" or "away from" the
nucleosome, the protein-DNA complex that folds the very long DNA strands
into the tiny nucleus of a cell and gives enzymes access to the DNA for
repair and for replication when the cell divides.
Washington State's senior author, Michael
J. Smerdon, explained, "Like a child's face, our DNA gets smudged up
all the time by environmental and bodily chemicals. Our work provides
additional details about how our cells work to clean the DNA up - to
correct our heredity molecule, the DNA helix that is within each living
cell." The explosion of research on DNA repair dates back less than a
decade, to the demonstration that some colon cancer and xeroderma
pigmentosum are linked to faulty DNA repair. Xeroderma pigmentosum is a
rare condition in which the skin is extremely sensitive to the sun and
other ultraviolet light, resulting in extreme freckling and aging.
A key element of the report is the
finding of a strong "down-regulation" of one of the repair
enzymes, DNA polymerase ß (pol ß) in the presence of the nucleosome.
This means that nucleosome formation on DNA can inhibit base excision
repair of a nucleosome-sequestered DNA lesion. Such down-regulation could
have huge biological implications, since repair of such DNA damage will be
blocked at the pol ß step. Such a blocking of repair will ultimately lead
to mutations or other genomic instability or will interrupt cell growth.
"This changes our thinking about
nucleosomes and base excision repair," Samuel Wilson, M.D., Ph.D.,
deputy director of NIEHS and its researcher on the project, said. "We
are still just scratching the surface of the study of cellular regulation,
but the potential seems clear. The findings demonstrate how close we are
to the day when, if the body fails to make the right regulatory
corrections, physicians may be able to step in and make them anyway. In
other words, to make corrections before diseases - a cancer or
Alzheimer's, for example - can develop."
Brian C. Beard, Ph.D., of WSU's School of
Molecular Biosciences carried out the study under the guidance of Drs.
Smerdon and Wilson.
The double-coil shape of the DNA molecule
which manages our heredity and directs our cells was described 50 years
ago. Almost immediately, it became clear that toxic agents in the
environment and in the body can produce adverse changes in the DNA.
Handily, however, these alterations are generally repaired by the body's
mechanisms, much the way "spell check" repairs misspelled words
on a computer. Actually, it is much more complicated than that:
In repairing some 10,000 to 20,000 DNA
adducts or lesions that occur each day in each of a human's 10 trillion
cells, repair enzymes travel up and down the double helix strands of DNA
until they find a damaged area. The enzymes cut out the lesion and fill
the gap with fresh DNA.
All this is performed in very tight
quarters. Each human cells has a strand of DNA that is almost two meters
long. This is tightly coiled in the bead-like nuclerosomes and densely
folded in order to fit inside the tiny nucleus of the cell.
Repairs are complicated by this compact
packaging, and Dr. Smerdon has shown that repair of damage cannot proceed
until the DNA is unfolded.
He said recently that understanding the
repair of DNA in specific regions of the packaged structure in the cell
nucleus is "crucial to understanding why certain DNA lesions are not
repaired for long times in human cells. Such 'long-lived' lesions can form
mutations and ultimately lead to cancer."
In 1978, Dr. Smerdon received a Young
Environmental Scientist Award from NIEHS, which has continued to support
his research. In 2002, NIEHS awarded Dr. Smerdon a ten-year $3.58 million
MERIT - Method to Extend Research in Time - award to further his
groundbreaking studies.
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