DNA damage - one cause

["Karam, Andrew" <Andrew_Karam@URMC.Rochester.edu>]

I just ran across this in a back issue of a University of Rochester
periodical.  Thought it might be of interest as it suggests that most DNA
damage is from the biological equivalent of "friendly fire".
Andy
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'Salvage Gene' at the Root of Mutations, Scientists Find 
In a discovery that may eventually open a major new avenue of cancer
prevention, a trio of Rochester researchers has found that most mutations in
yeast are caused by the activity of an obscure enzyme that acts to salvage
irreparably damaged DNA. The enzyme, REV1, helps a cell evade its own
stringent quality control and opens the door to mutations. 
The scientists, who admit they were surprised at their finding, had set out
to learn more about a family of enzymes whose function it is to repair
faulty DNA in yeast. When the researchers damaged the yeast's DNA and then
studied its coping mechanisms, they made a startling discovery: One of the
repair enzymes, REV1, turns out to be responsible for almost all of the
mutations that occur in DNA. 
"We found something that we weren't at all looking for," says David Hinkle,
associate professor of biology. "This was really a bombshell." Also working
on the project, funded by the National Institutes of Health, are
postdoctoral fellow John Nelson and Christopher Lawrence, professor of
biophysics. 
The vast majority of mutations come not from such much touted sources as
asbestos and pesticides or other environmental factors, but from normal
chemistry that goes on within our bodies, the researchers note. "DNA is not
a stainless steel molecule," Lawrence points out. "It is susceptible to
damage as a natural part of its existence." 
The most common form of DNA damage is sporadic loss of individual molecules
of adenine and guanine--two of the four bases that encode genetic
information along a strand of DNA. Such losses result in genetic gaps known
as "abasic" sites. 
"Formation of these abasic sites," says Hinkle, "is, in fact, one of the
most common occurrences in our cells," taking place every day in about
10,000 to 20,000 of the three trillion DNA bases in each cell. Uncorrected
abasic sites can be lethal to cells because they act as vast potholes,
halting the polymerase enzymes that usually zip along a strand of DNA during
replication. If a cell is unable to replicate its DNA, it will eventually
die. 
Cells usually avoid this fate--as well as mutations--by accurately repairing
abasic sites in a variety of ways. But very rarely these cellular efforts at
quality control fail, and it's at this desperate stage that REV1, the enzyme
discovered by Nelson, Hinkle, and Lawrence, causes a mutagenic bypass. 
"There's every reason to believe that mutagenesis in humans will prove to be
very similar to that in yeast," says Lawrence, noting that Rochester
scientists have already identified similar gene sequences in human DNA. "And
mutagenesis is at the heart of cancer, which is thought to occur because
mutations permit precancerous cells to overcome the genetic defenses against
unlimited cell proliferation and migration." People with a genetic
predisposition to cancer could be given drugs to knock out the REV1 enzyme,
stopping mutations before they arise. 
Says Lawrence, a longtime professor of biophysics, the discovery "was one of
those wonderful pieces of serendipity that crop up in science and make it so
enjoyable."
==========================================
Andrew Karam, CHP              (716) 275-1473 (voice)
Radiation Safety Officer          (716) 275-3781 (office)
University of Rochester           (716) 256-0365 (fax)
601 Elmwood Ave. Box HPH   Rochester, NY  14642

Andrew_Karam@URMC.Rochester.edu
http://Intranet.urmc.rochester.edu/RadiationSafety

Mathematics may be compared to a mill of exquisite workmanship which grinds
you stuff of any degree of fineness; but, nevertheless, what you get out
depends on what you put in; and as the grandest mill in the world will not
extract wheat-flour from peascods, so pages of formulae will not get a
definite result out of loose data.  (T.H. Huxley, 1869)

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