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Scientists Uncover Workings of Cancer-Linked DNA-Repair Mechanism

New findings from The Scripps Research Institute (TSRI) illuminate an important but little-understood mechanism that helps repair severe DNA damage in our cells. The repair mechanism has been implicated in gross chromosomal rearrangements that turn cells cancerous. But the TSRI scientists found evidence that this repair mechanism, though error-prone, has an overall protective role.

“It’s a double-edged sword, but we suspect that the mechanism causes cancer-promoting chromosomal rearrangements only when it loses its normal regulation in the cell,” said Xiaohua Wu, associate professor in TSRI’s Department of Molecular and Experimental Medicine and principal investigator for the study. “Knowing the details of that regulation and how it is lost could lead us to a better understanding of the origins of cancer.”

Normal or Abnormal Repair Process?

The study, published recently in the Proceedings of the National Academy of Sciences, examined a mechanism called microhomology-mediated end joining (MMEJ). This is one of several known repair systems in cells that can reconnect a segment of DNA after it has been completely severed through its two complementary strands.

Such “double strand breaks” in DNA may be caused by ionizing radiation or toxins, or even by snags in the DNA replication process during cell division. If these breaks are not repaired properly, they will likely lead to premature cell death or even cancer—which is why inherited deficiencies in double-strand-break repair systems tend to accelerate aging, heighten people’s sensitivity to X-rays and/or boost cancer risk.

Very little has been known about MMEJ. But cancer frequently arises from a misrepair of a double-stranded DNA break in a cell, and biologists have found that such misrepairs often bear MMEJ’s hallmarks.

“A big question for us was whether MMEJ is a normal repair process in cells or just an abnormal one that leads to cancer,” said Wu, whose TSRI laboratory studies DNA repair mechanisms.

Two postdoctoral fellows in the Wu lab, Lan Truong and Yongjiang Li, set up complex experiments to monitor MMEJ in cells and found evidence that the process is active during normal cellular operations, and especially during DNA replication. “MMEJ is utilized at a significant rate even when other less error-prone mechanisms are available,” said Truong.

An Error-Prone Mechanism with a Payoff

MMEJ is error-prone because it works by trimming back DNA strands—permanently deleting genetic information—to expose short sequences (microhomologies) that will stick to each other to mediate a reconnection.

Why would mammals have evolved the use of such an error-prone DNA-repair mechanism even when other less error-prone mechanisms are available?

“We think that MMEJ offers a simpler pathway and shorter repair time than the other major repair mechanism with which it competes,” said Li. That other repair mechanism, known as homologous recombination, is relatively error-free but requires a lengthier processing of severed DNA ends and thus more time—often during the crucial moments of cell division.

Truong’s and Li’s experiments also suggest that MMEJ can operate in situations where another major repair mechanism, classical non-homologous end-joining, is largely excluded.

The payoff of MMEJ is that the cell keeps its genome intact and probably stays alive and functional. The downside comes from the deletions. “But we think that our cells on the whole can afford the small deletions normally caused by MMEJ because these are likely to occur within the non-coding sequences that make up a large fraction of our DNA,” said Wu.

Truong and Li’s experiments turned up evidence that MMEJ is tightly regulated in cells—somewhat as homologous recombination is regulated. The researchers suspect that the failure of this regulation is what explains most MMEJ misrepairs and resulting cancers. “The next big question for us is how MMEJ is regulated to just do the right kind of repairs and avoid the gross errors that can lead to cancer,” Wu said.

Other contributors to the study, “Microhomology-Mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells,” were Patty Yi-Hwa Hwang, Jing He, Hailong Wang and Niema Razavian of the Wu laboratory; and Linda Z. Shi and Michael W. Berns of the Berns laboratory at the University of California, San Diego. For more information on the paper, see

The study was supported by the National Institutes of Health (grants CA102361, GM080677, CA140972 and CA102361-07S1).

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“Knowing the details of [the mechanism’s] regulation and how it is lost could lead us to a better understanding of the origins of cancer,” says Associate Professor Xiaohua Wu (left), shown here with Research Associates Yongjiang Li (center) and Lan Truong. (Photo by Cindy Brauer.)