How Chronic Stress Can Induce Genomic Damage

A mechanism has been elucidated that helps explain how prolonged states of stress can cause genomic damage that has been linked to various diseases including cancer.

In response to stress the body increases production of certain hormones including the catecholamines, a group of sympathomimetic amines (including dopamine, epinephrine, and norepinephrine), that are derived from the amino acid tyrosine and contain a catechol or 3,4-dihydroxybenzene group. Their release at sympathetic nerve endings increases the rate and force of muscular contraction of the heart, thereby increasing cardiac output; constricts peripheral blood vessels, resulting in elevated blood pressure; elevates blood glucose levels by hepatic and skeletal muscle glycogenolysis; and promotes an increase in blood lipids by increasing the catabolism of fats.

In the current study, investigators at Duke University (Durham, NC, USA) and The Scripps Research Institute (Jupiter, FL, USA) examined how chronic elevation of chatecholamine levels was related to disease development.

They reported in the August 21, 2011, online edition of the journal Nature that increased catecholamines could trigger DNA damage and suppress levels of the tumor suppressor protein, p53. The molecular mechanism behind these effects linked the catecholamines with beta-arrestin-1 proteins (Arrb1) and beta2-adrenoreceptors (beta2ARs). Under stress, adrenaline stimulates beta2ARs, which are expressed throughout the body, including sex cells and embryos. Through a series of complex chemical reactions, the activated receptors recruit beta-arrestin-1, creating a signaling pathway that leads to catecholamine-induced degradation of p53.

Catecholamine-induced DNA damage was abrogated in Arrb1-knockout mice, which showed preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring’s genome.

“Our results provide a possible mechanistic 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 senior author Dr. Robert J. Lefkowitz, professor of medicine at Duke University. “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 deleterious DNA-damaging consequences of long-term stress in humans.”

Related Links:
Duke University
The Scripps Research Institute