Fox Chase Study Reveals Mechanism for Repairing DNA Damage Caused by Environmental Triggers

PHILADELPHIA (November 17, 2022)—It’s long been known that DNA damage caused by environmental triggers, as well as other sources of oxidative stress, contribute to the development and progression of a wide variety of cancers. Now a new study by a Fox Chase Cancer Center scientist provides new insight into how an enzyme called apurinic/apyrimidinic 1 (APE1) repairs this damage.

The study showed, for the first time, how APE1 binds to a common oxidative DNA lesion and sculpts the DNA to hold it in place for repair. It identified the key regions of the enzyme that are involved in the repair process, findings that could help lay the groundwork for future therapeutic treatments targeting this process.

“The more we understand how this enzyme works, the better we are able to design a drug or manipulate that mechanism to modulate its activity to enhance or decrease the effects of DNA damage,” said Amy Whitaker, PhD, an assistant professor in the Nuclear Dynamics and Cancer research program at Fox Chase. Whitaker began the research as a postdoctoral fellow at the University of Kansas Medical Center and completed and published it after moving to start her independent lab at Fox Chase.

Oxidative stress is caused by a wide variety of environmental triggers, from smoking, to UV radiation, to the food that people eat. The human body is constantly repairing damaged DNA, but when it is exposed to extra stressors like disease or environmental pollutants, that repair process may not be able to keep up with the damage and mutations can occur.

Whitaker’s study looked at a type of DNA lesion caused by oxidative stress called 8-oxoG. Scientists already knew that the APE1 enzyme repaired damage by removing this lesion from the end of a DNA strand. However, the exact mechanism it used to do this was not understood.

For her study, Whitaker first used a technique called X-ray crystallography, which enables scientists to determine the 3D structure of proteins and biological macromolecules. Through this process, researchers were able to generate images of the atomic structure of APE1 after binding damaged strands of DNA for repair.

They noticed two key details. First, they saw that the APE1 protein bends the DNA at the point of damage. Second, they saw that the enzyme was “hugging” the frayed end of the DNA to hold the DNA helix open while the repair took place. In a sense, the APE1 was sculpting the flexible strand of DNA into position for repair, Whitaker said. Once the APE1 was in place, researchers noticed that the enzyme structure included an open binding pocket that fit against the damaged portion of the DNA.

In the second part of the study, researchers created APE1 variants to see what happened when key regions of the protein identified in the structures were removed. They found that when they removed the “hugging” structure that kept the DNA open, it significantly decreased the enzyme’s ability to repair lesions. At the same time, when they removed regions of the binding pocket, the repair activity increased.

Whitaker said the findings could have implications not just for new treatments to improve DNA repair capacity, but also for potentially increasing damage from existing cancer treatments that intentionally attack DNA in order to disrupt tumor growth.

“Findings like these help us to rationally design therapeutics that target specific activities in a multifunctional protein,” she said, adding that follow-up research could include testing these functions in cellular or animal studies.

The study, Processing Oxidatively Damaged Bases at DNA Strand Breaks by APE1,” was published in Nucleic Acids Research.

 

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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