Leona Samson - Too much of a good thing
Excessive DNA repair can lead to retinal degeneration
Anne Trafton, News Office
January 9, 2009
A naturally occurring DNA repair system that normally protects cells from
damage can cause retinal degeneration and blindness when
overstimulated, according to a new study by MIT researchers.
The research team found that relatively low-level exposure to an
environmental toxic agent provoked very active DNA repair that led to
surprisingly high rates of retinal degeneration in mice -- much higher than in
mice lacking the same DNA repair pathway. The work raises the possibility
of developing treatments for retinal degeneration by blocking a particular
DNA repair pathway.
"Under some circumstances, too much DNA repair is not a good thing and
could actually be a bad thing," said Leona Samson, co-director of MIT's
Center for Environmental Health Sciences, professor of biology and
biological engineering, and senior author of a paper on the work appearing
online in the Proceedings of the National Academy of Sciences this week.
Samson and her colleagues studied a pathway involving an enzyme called
Aag. The enzyme has a human analogue called AAG that may play a role in
retinitis pigmentosa (RP), a group of genetic eye disorders that lead to
blindness and affect between 50,000 and 100,000 people in the United
Aag plays a critical role in DNA repair, snipping out DNA bases damaged
by environmental toxic agents, such as those found in tobacco smoke and
fuel exhaust. Later on, the damaged bases are replaced with new ones.
Under normal levels of environmental toxic agent exposure, the system
functions effectively. However, the researchers found that if mice were
exposed to a higher (but non-lethal) level of toxic agent, the system backfired. Aag cuts out so many bases that the rest of the DNA repair
system cannot keep up, leading to death of the rod and cone cells that
make up the retina.
This malfunction in the DNA repair pathway occurs only in certain body
tissues, including the retina, and only in mice with normal Aag levels. Mice
lacking Aag do not exhibit retinal degeneration, while mice with high Aag
levels had even higher levels of retinal degeneration.
Lead author of the paper is Lisiane Meira, a former research scientist in the
Center for Environmental Health Sciences (CEHS). Other authors are
Catherine Moroski-Erkul, technical assistant in CEHS; Stephanie Green,
former graduate student in biological engineering; Jennifer Calvo, research
scientist in CEHS; Dharini Shah, postdoctoral associate in CEHS; and
Roderick Bronson, veterinary pathologist at Harvard Medical School.
The research was funded by the National Institutes of Health, and Samson
is an American Cancer Society Professor.
MIT News article.