At last, a reason why stress causes DNA damage

For years, researchers have published papers that associate chronic stress with chromosomal damage. Now researchers at Duke University Medical Center have discovered a mechanism that helps to explain the stress response in terms of DNA damage.

"We believe this paper is the first to propose a specific mechanism through which a hallmark of chronic stress, elevated adrenaline, could eventually cause DNA damage that is detectable," said senior author Robert J. Lefkowitz, M.D., James B. Duke Professor of Medicine and Biochemistry and a Howard Hughes Medical Institute (HHMI) investigator at Duke University Medical Center.

The paper was published in the Aug. 21 online issue of Nature. In the study, mice were infused with an adrenaline-like compound that works through a receptor called the beta adrenergic receptor that Lefkowitz has studied for many years. The scientists found that this model of chronic stress triggered certain biological pathways that ultimately resulted in accumulation of DNA damage.

P53 is a tumor suppressor protein and is considered a "guardian of the genome" -- one that prevents genomic abnormalities. In the current study, the scientists found a molecular mechanism through which adrenaline-like compounds acted through both G-protein and the beta-arrestin pathways to trigger DNA damage.

The Nature publication showed that the infusion of an adrenaline-like compound for four weeks in the mice caused degradation of p53, which was present in lower levels over time. The study also showed that the DNA damage was prevented in mice lacking beta-arrestin 1. Loss of beta-arrestin 1 stabilized cellular levels of p53 both in the thymus, an organ that strongly responds to acute or chronic stress, and in the testes, where paternal stress might affect an offspring`s genome.

Future studies planned by the Lefkowitz laboratory include studying mice that are placed under stress (restrained), thus creating their own adrenaline or stress reaction to learn whether the physical reactions of stress, rather than an influx of adrenaline in the lab as was done in the current study, also leads to accumulation of DNA damage. The study was supported by the Howard Hughes Medical Institute.


/Duke Health/