May 14, 2009
MicroRNA assume new role in DNA repair
Dipanjan Chowdhury and colleague Yunfeng Pan Among their many talents as message couriers and gene
regulators, microRNA molecules also help control the repair of
damaged DNA within cells, Dana-Farber and Harvard Medical School
scientists report in the May issue of Nature Structural & Molecular
Biology.
The finding not only demonstrates the unexpected versatility of
microRNA (miRNA) in the life of cells, but also may lead to new
tests for determining tumors' aggressiveness and likely response to
therapy. Because radiation and chemotherapy kill cancer cells by
damaging their genetic material, knowledge of the DNA repair
mechanism may suggest novel solutions to the problem of drug
resistance, in which tumors gain the ability to withstand drugs
that initially were effective against them.
"MicroRNAs are gaining an increasing amount of attention in
cancer research, but there hasn't been any evidence that they play
a role in DNA repair," says Dana-Farber's Dipanjan Chowdhury, PhD,
senior author of the journal paper and co-corresponding author with
Judy Lieberman, MD, PhD, of Harvard. "This study is the first to
provide that evidence."
To find out whether miRNAs are involved in DNA repair, Chowdhury
and his associates – including co-lead author Yunfeng Pan and Lisa
Moreau, both of Dana-Farber – collected several sets of mature
blood cells, which have a reduced ability to repair DNA damage, and
identified the types of miRNA within them. They found that
different types of blood cells had a small set of miRNAs in common – an overlapping "miRNA signature."
One of the strongest links among the cell groups was a high
level of a miRNA known as miR-24. This caused a slowdown in
production of a DNA-mending protein called H2AX, interfering with
the efficiency of DNA repair.
The discovery raises the issue of why a cell might want to give
its DNA repair crew a break from time to time. Since DNA contains
the operating instructions for cell division (and other processes),
it would seem prudent for cells to be constantly ready to fix
broken DNA, much as an electric power company has repair teams
always available. In fact, however, during the "resting phase" of
cell division - when genes involved in division are inactive –
repairs are unnecessary. Hence the need for molecules like miRNAs
to temporarily quiet the repair response.
As investigators identify additional miRNAs involved in DNA
repair, tumors may one day be routinely analyzed for miRNA content.
"A tumor's miRNA profile may serve as a marker for how aggressive
the malignancy is likely to be, and how vulnerable it will be to
DNA-damaging agents," Chowdhury comments.
The research may also result in new forms of therapy. Drugs that
impede cancer cells' ability to repair their DNA could make these
cells more vulnerable to radiation and chemotherapy. Recent studies
in primates have shown that some pharmacological compounds can
alter miRNA activity. Such compounds could potentially reverse
tumors' resistance to conventional therapies.
– Rob Levy
Robert_Levy@dfci.harvard.edu