• May 14, 2009
    MicroRNA assume new role in DNA repair

    dipanjan-chowdhury-and-yunfeng-pan.jpgDipanjan 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 

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