A protein previously suspected in inhibiting DNA repair
actually promotes it and prevents cancer, according to a study by researchers
from the University of Texas M. D. Anderson Cancer Centre.
The protein, HMGB1 has long been known to attach to sites of
damaged DNA and was believed to prevent DNA repair.
"That did not make sense to us, because HMGB1 is a
chromosomal protein that''s so abundant that it would be hard to imagine cell
repair happening at all if that were the case," said Vasquez.
During the study, Vasquez and Sabine Lange, a doctoral
candidate in the Graduate School of Biomedical Sciences analysed the protein''s
impact on DNA restoration that includes access to damage, repair and
repackaging of the original structure, a combination of DNA and histone
proteins called chromatin.
First, they knocked out the gene mouse embryonic cells and
then exposed cells to two types of DNA-damaging agents. One was UV light, the
other a chemotherapy called psoralen that's activated by exposure to darker,
low frequency light known as UVA.
In both cases, the cells survived at a steeply lower rate
after DNA damage than did normal cells.
Later they exposed HMGB1 knockout cells and normal cells to
psoralen and assessed the rate of genetic mutation.
The knockout cells had a mutation frequency more than double
that of normal cells, however, there was no effect on the types of mutation
Knock out and normal cells were then exposed to UV light and
suffered the same amount of damage. However, those with HMGB1 had two to three
times the repair as those without.
Vasquez said that this showed that HMGB1 worked by summoning
other DNA repair factors to the damaged site.
However, HMGB1''s role in repair is crucial to drugs under
development to block the protein, Vasquez said.
The protein also plays a role in inflammation, so it''s
being targeted in drugs under development for rheumatoid arthritis and sepsis.
"Arthritis therapy involves long-term treatment,"
Vasquez said. "Our findings suggest that depleting this protein may leave
patients more vulnerable to developing cancer."
The study appears online this week in the Proceedings
of the National Academies of Science.