For the first time, UNC School of Medicine scientists led by Nobel laureate Aziz Sancar analyzed whole-genome DNA repair in an animal over 24 hours to find which genes were repaired, where exactly, and when, laying the groundwork for a more precise use of anti-cancer drugs.
We all have tiny, protein-operated clocks inside our cells that operate based upon the 24-hour day cycle. These circadian clocks are important for the proper biological function of different organs – heart, liver, lungs, brain, skin. Yet, we don’t know exactly how they interact with other basic and crucial biology, such as DNA repair – the process our cells constantly undergo because we are perpetually bombarded with stuff that wrecks DNA. Sunlight, for instance.
The UNC School of Medicine lab of Nobel laureate Aziz Sancar works on these two fronts of circadian clock and DNA repair. Sancar’s lab developed a way to measure the repair of DNA damage caused by cisplatin – a common anti-cancer drug. And for the first time, his lab measured DNA repair after cisplatin treatment over the course of an entire 24-hour circadian cycle throughout an entire genome of a mammal.
Published in the Proceedings of the National Academy of Sciences, the researchers found what sites in the genome were repaired, what specific genes were repaired, and when.
“We found there are close to 2,000 genes, different parts of which are repaired at different times of day, depending on the gene,” said Sancar, senior author and the Sarah Graham Kenan Distinguished Professor of Biochemistry and Biophysics. “We believe understanding these circadian patterns and kinetics throughout the genome and in various organs will help us discover and develop better treatment regimens for people with cancer.”
Cisplatin is a short-term intravenous chemotherapy to treat solid malignancies, including lung cancer, testicular cancer, head and neck cancer, ovarian cancer, lymphomas, bladder cancer, cervical cancer, and germ cell tumors. Used against nearly 50 percent of solid tissue cancers, cisplatin kills cancer cells by binding to particular parts of the cancer cell’s DNA. But cisplatin is toxic to the kidneys, liver, and nervous system – including the brain. These side effects limit the drug’s usefulness.
Originally published May 9, 2018.