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Environmental Factor, June 2014

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Fast test for measuring DNA repair

By Anne Trafton

Zachary Nagel, Ph.D.

Nagel said the new test could be used to screen for new drugs that inhibit or enhance DNA repair. Inhibitors could target tumors to make them more susceptible to chemotherapy, while enhancers could help protect people who have been accidentally exposed to DNA-damaging agents, such as radiation. (Photo courtesy of Samson Lab)

Leona Samson, Ph.D.

Samson is an Uncas and Helen Whitaker Professor, American Cancer Society Research Professor, and a member of the MIT Department of Biological Engineering, Department of Biology, Center for Environmental Health Sciences, and David H. Koch Institute for Integrative Cancer Research. (Photo courtesy of Samson Lab)

DNA repair pathways

MIT biological engineers have developed a way to test several different DNA repair pathways in one cell. In each of these images, the cell is producing a different fluorescent protein, indicating whether it has successfully repaired one of four different types of DNA damage. (Photo courtesy of Samson Lab)

A new test developed by an NIEHS-funded research team at the Massachusetts Institute of Technology (MIT) can analyze four types of DNA repair capacity simultaneously. This test could help determine an individual’s risk of developing cancer and help doctors predict how a given patient will respond to chemotherapy drugs.

Previous tests have been able to evaluate only one DNA repair system at a time. Described in a paper (http://www.ncbi.nlm.nih.gov/pubmed/24757057)   published in the journal Proceedings of the National Academy of Sciences, the test of all four systems takes less than 24 hours.

Damage to DNA

DNA is under constant attack from many sources, including environmental pollutants, ultraviolet light, and radiation. Cells have several major DNA repair systems that can fix this damage, which may lead to cancer and other diseases if not repaired properly.

The effectiveness of these repair systems varies greatly from person to person. Scientists believe that these differences may explain why some people get cancer, while others exposed to similar DNA-damaging agents do not.

Measuring each repair system takes expertise, time, and is labor-intensive, said Zachary Nagel, Ph.D., an MIT postdoctoral researcher and lead author of the paper. “What we wanted to do was come up with one way of measuring all DNA repair at the same time, so you have a single readout that’s easy to measure,” he said.

The research team, led by Leona Samson, Ph.D. (http://web.mit.edu/be/people/samson.shtml)  used the new test to measure DNA repair in a type of human blood cell. They found huge differences among samples from 24 healthy volunteer donors, especially in one repair system where cells from some volunteers were more than 10 times more efficient than those from others.

“None of the cells came out looking the same. They each have their own spectrum of what they repair well and what they don’t repair well,” said Samson, who is an NIH Pioneer (https://commonfund.nih.gov/pioneer/index)  awardee.

Future uses may predict risk, screen treatments

Scientists have identified links between DNA repair and neurological, developmental, and immunological disorders. But useful, predictive tests for DNA repair have not been developed, largely because it has been impossible to rapidly analyze several different types of DNA repair capacity at once.

Samson’s lab is now working on adapting the new test. They are researching whether the test could be used to identify people who are at higher risk for diseases and potentially enable prevention or earlier diagnosis. Other potential uses include predicting a patient’s response to chemotherapy drugs, which often work by damaging the DNA of cancer cells, and determining how much radiation treatment a patient may tolerate.

Another important application for this test could be studying fundamental biological processes, such as how cells recruit backup repair systems to fill in when another pathway is overwhelmed, says Samuel Wilson, M.D., head of the NIEHS DNA Repair and Nucleic Acid Enzymology Group.

“There’s an opportunity to use these multiplexed plasmids in biological assays where several repair pathways can be probed at the same time, offering a very advanced tool to allow us to make much better interpretations about the repair status of a cell,” said Wilson, who was not part of the research team.

Citation: Nagel ZD, Margulies CM, Chaim IA, McRee SK, Mazzucato P, Ahmad A, Abo RP, Butty VL, Forget AL, Samson LD. (http://www.ncbi.nlm.nih.gov/pubmed/24757057)  2014. Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Proc Natl Acad Sci U S A 111(18):E1823-E1832.

(This story was adapted from an article (http://newsoffice.mit.edu/2014/fast-way-to-measure-dna-repair-0421)  by Anne Trafton, a writer with MIT News, the MIT News Office publication.)




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