microRNA Plays Role In DNA Repair
Among their many roles as message couriers and gene regulators, microRNA molecules also help control the repair of damaged DNA within cells, Dana-Farber Cancer Institute 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 a tumor's aggressiveness and likely response to different therapies.
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 develop 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 Dipanjan Chowdhury, PhD, of Dana-Farber, who is senior author of the paper and the co-corresponding author with Judy Lieberman, MD, PhD, of the Immune Disease Institute in Boston. "This study is the first to provide that evidence."
To find out whether miRNAs are involved in DNA repair, Chowdhury and his colleagues collected several sets of mature blood cells, which have a low ability to repair DNA damage, and identified the types of miRNA within them. They found that different types of blood cells had small set of miRNAs in common — an overlapping "miRNA signature."
One of the strongest links among the cell groups was an miRNA known as miR-24. The investigators discovered that the cells had high levels of miR-24, which caused a slowdown in production of a DNA-mending protein called H2AX, impacting 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.
The implications of the discovery for the treatment of cancer and other genetically-caused diseases are compelling, Chowdhury says. As researchers 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 such 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.