Scientists now know how some tumor cells overcome DNA damage that should kill them. The malignant cells make backup copies of their chromosomes and rewire their genetics for survival.

The finding is important because it points out how cancerous cells survive and thrive, even though their DNA is abnormal — hinting at a way to potentially send them spiraling into death.

Bing Shen (Photo by Walter Urie)

A research team led by City of Hope’s Binghui Shen, Ph.D., professor and chair of the Department of Radiation Biology, studied tumor cells that have mutations in a repair gene called FEN1. A broken FEN1 gene means the cells lack the ability to repair certain types of DNA damage. A subset of some cancers have this sort of FEN1 defect.

“When cells suffer damage to their DNA, they normally must choose one of two paths: Repair the DNA or die,” Shen said. If the cells cannot repair the DNA damage, they usually sacrifice themselves by ramping up genes that force them into suicide, a process called apoptosis.

So how does cancer avoid that choice? Shen’s team believes the answer lies in cancer’s abnormal core.

The scientists watched in the lab as cancerous cells with FEN1 mutations struggled to repair their damaged DNA. During the process, the cells accidentally made extra copies of their chromosomes. These chromosomes carried extra copies of other DNA repair genes. The genes became active, helping pick up just enough of the slack from the failing FEN1 genes to keep the cells going despite DNA damage.

In addition, the scientists found that the diseased cells shut down the activity of a key gene, called p53, that normally would push the cells to undergo apoptosis. What surprised them, however, was how the gene was shut down, according to Li Zheng, Ph.D., assistant research professor in the Department of Radiation Biology and first author on the study.

“We found that the p53 gene wasn’t mutated as expected, but rather the cell reduced expression of p53 target genes such as p21 through epigenetic mechanisms,” Zheng said. Epigenetics uses chemical changes to DNA and chromosomes to turn genes on and off.

The findings show that the malignant cells’ ability to avoid apoptosis is no accident, but rather it is a result of the cells actively overcoming their internal kill switch.

The researchers hope the insight will point to epigenetic drugs that might reverse the silencing of p53 and send cancer cells back down the path of suicide.

The results were published in the May 8 issue of Nature Communications.

Other authors on the study include Huifang Dai, Mian Zhou, M.D., Ph.D., Xiaojin Li, M.D., Ph.D., Changwei Liu, Zhigang Guo, Ph.D., Xiwei Wu, M.D., Ph.D., Jun Wu, Ph.D., Charles Wang, M.D., Ph.D., M.P.H., Qin Huang, M.D., Ph.D., Gerd P. Pfeifer, Ph.D., Julio Garcia-Aguilar, M.D., Ph.D., and John Zhong, Ph.D.

The study was supported by the National Cancer Institute and the U. S. Army RDECOM Acquisition Center, Natick Contracting Division.

NIH grants: CA085344, CA073764 and CA33572.