Cells Need “Repair Centers” to Mend Severely Damaged DNA

New findings about the way cells mend severe DNA damage within “repair centers” could lead to improvements in cancer treatment, say researchers at Columbia University’s Vagelos College of Physicians and Surgeons. The findings were published June 20 in the journal Nature.

A cell’s DNA can be damaged 100,000 times a day, and the damage can lead to mutations that cause cancer.

“But cells have ways to repair the damage, and as researchers learn more about these techniques, we may be able to exploit them to develop new anti-cancer therapies,” says Jean Gautier, PhD, professor of genetics & development in the Institute for Cancer Genetics at Columbia University Vagelos College of Physicians and Surgeons and associate director of research at Columbia’s Herbert Irving Comprehensive Cancer Center. Already, based on research about DNA repair, drugs called PARP inhibitors have been approved by the FDA for use in breast and ovarian cancers caused by BRCA mutations.

The most dangerous type of DNA damage occurs when both strands of the DNA helix are severed. To repair the damage, cells often move the broken DNA ends to clusters with other broken ends, but the reason for this and how it happens is unknown.

Gautier and his team used mouse and human tumor cells to investigate how the broken DNA ends are moved before they are mended via a pathway called homology-directed repair.

They first found that two proteins–WASP and Arp2/3–work together to create actin filaments that push the broken DNA ends into the repair clusters. Actin filaments are known to move cellular components in the cell’s cytoplasm. “We knew actin filaments also existed in the nucleus, but their role was elusive until our study,” says Gautier.

When the researchers prevented the formation of actin filaments, DNA repair was reduced by about 50 percent. “This showed that a cell needs these 'repair factories' for the repair process to work well,” Gautier says.

The new finding could potentially lead to improvements in cancer treatment, Gautier says. Although double-strand breaks are implicated in cancer development, many cancer treatments, including radiation therapy, work by causing lethal amounts of DNA damage that leads to cell death.

“If we have a better understanding of how double-strand breaks are repaired, we may be able to create more targeted treatments that prevent tumor cells from repairing otherwise lethal DNA damage.