Scripps Research Scientists Help Pinpoint Cause of Stress-Related DNA Damage - Findings Suggest New Model for Developing Novel Therapeutic Approaches.

Working with a team of researchers from Duke University, scientists from the Jupiter campus of The Scripps Research Institute have helped identify a molecular pathway that plays a key role in stress-related damage to the genome, the entirety of an organism's hereditary information.

Derek Duckett

The new findings, published in the journal Nature on August 21, 2011,  explained the development of certain human disorders, and also offered a potential model for prevention and therapy.

While humans are built to respond to stress (the “fight or flight” response, which lasts only a few minutes and raises heart rate and blood glucose levels), the response itself can cause significant damage if maintained over long periods of time. When stress becomes chronic, this natural response can lead to a number of disease-related symptoms including peptic ulcers and cardiovascular disorders.

To make matters worse, evidence indicates that chronic stress eventually leads to DNA damage, which can result in various neuropsychiatric conditions, miscarriages, cancer and even aging itself.

“Precisely how chronic stress leads to DNA damage is not fully understood,” said Derek Duckett, associate scientific director of the Translational Research Institute at Scripps Florida. “Our research now outlines a novel mechanism highlighting b-arrestin-1 as an important player.”

The results of the research provide a possible basis for several recent reports suggesting that significant risk reductions for diseases such as prostate cancer, lung adenocarcinoma,and Alzheimer’s disease may be associated with blockade of this particular stress-response pathway by beta blockers, said Robert J. Lefkowitz, a Duke University professor of medicine who led the study.

“Although there are most likely numerous pathways involved in the onset of stress-related diseases, our results raise the possibility that such therapies might reduce some of the DNA-damaging consequences of long-term stress in humans.”

A Newly Discovered Mechanism
The newly uncovered mechanism involves β-arrestin-1 proteins, β2-adrenoreceptors (β2ARs), and the catecholamines, the classic fight-or-flight hormones released during times of stress—adrenaline, noradrenaline, and dopamine.

Arrestin proteins are involved in modifying the cell’s response to neurotransmitters, hormones and sensory signals; adrenoceptors respond to the catecholamines noradrenaline and adrenaline.

Under stress, the hormone adrenaline stimulates β2ARs expressed throughout the body, including sex cells and embryos. Through a series of complex chemical reactions, the activated receptors recruit β-arrestin-1, creating a signaling pathway that leads to catecholamine-induced degradation of the tumor suppressor protein p53, sometimes described as “the guardian of the genome.”

The new findings also suggest that this degradation of p53 leads to chromosome rearrangement and a build-up of DNA damage both in normal and sex cells. These types of abnormalities are the primary cause of miscarriages, congenital defects, and mental retardation, the study noted.