[Editors] MIT team probes inflammation, disease link

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
http://web.mit.edu/newsoffice/www

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MIT team probes inflammation, disease link
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For Immediate Release
MONDAY, JULY 31, 2006
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

PHOTO, GRAPHIC AVAILABLE


CAMBRIDGE, Mass.--New research at MIT may help 
scientists better understand the chemical 
associations between chronic inflammation and 
diseases such as cancer and atherosclerosis. The 
work could lead to drugs that break the link 
between the two.

When an infection occurs, immune cells flock to 
the area and secrete large amounts of highly 
reactive chemicals to combat the invader. But, 
these inflammatory chemicals also attack normal 
tissue surrounding the infection and damage 
critical components of cells, including DNA. 
During chronic inflammation, that damage may lead 
to mutations or cell death and even to cancer and 
other diseases.

MIT researchers, led by toxicology graduate 
student Yelena Margolin of the Biological 
Engineering Division, have discovered that the 
DNA damage produced by one of these inflammatory 
chemicals, nitrosoperoxycarbonate, occurs at 
unexpected locations along the DNA helix. The 
finding counters the prevailing theory about 
where the DNA damage occurs and may shed light on 
new ways to diagnose and combat inflammation.

"We need to understand the mechanisms of 
inflammation in order to make new drugs that will 
break the link between inflammation and disease 
and to develop predictive biomarkers," said Dr. 
Peter Dedon, professor of toxicology and 
biological engineering and associate director of 
the Biological Engineering Division at MIT. "One 
of our goals is to develop biomarkers that can 
tell if you have inflammation and to define its 
extent, severity and location."

Margolin, Dedon and their colleagues at MIT and 
New York University reported their findings in a 
recent advance online issue of Nature Chemical 
Biology.

For years researchers have studied how the 
chemicals associated with the body's response to 
infection can damage DNA. That process begins 
with the removal of an electron from guanine, one 
of the four base building blocks that determine 
the genetic code in DNA. That removal is called 
oxidation, and guanine is the most easily 
oxidized of the four building blocks.

The prevailing theory has been that oxidation 
occurs most frequently when the guanine is 
sandwiched between two other guanine bases in the 
DNA helix.

By using comprehensive chemical screening and 
analysis of the frequency of DNA damage, the 
researchers found that a chemical produced during 
inflammation, nitrosoperoxycarbonate, actually 
caused oxidative damage at guanines that were 
supposed to be the least easily oxidized. The 
damage did not occur in clusters of guanine as 
expected, but rather at locations where guanine 
precedes cytosine, another of the four building 
blocks.

"That observation overturns the prevailing theory 
for predicting the location of DNA damage in the 
genome and complicates our understanding of the 
basis for diseases arising from chronic 
inflammation," said Dedon. "But it is likely to 
stir up discussions in the DNA damage and 
mutagenesis fields that could help us better 
understand the consequences of inflammation."

Margolin's and Dedon's colleagues on the paper 
are Jean-Francois Cloutier, auxiliary professor 
of pharmaceutical chemistry at Université Laval 
in Québec and formerly of the Dedon lab; Vladimir 
Shafirovich, research professor of chemistry at 
New York University; and Nicholas Geacintov, 
professor of chemistry and department chair at 
New York University.

The research was funded by the National Cancer Institute.

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Elizabeth A. Thomson
Assistant Director, Science & Engineering News
Massachusetts Institute of Technology
News Office, Room 11-400
77 Massachusetts Ave.
Cambridge, MA  02139-4307
617-258-5402 (ph); 617-258-8762 (fax)
<thomson at mit.edu>

<http://web.mit.edu/newsoffice/www>
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