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.
"This could give us a plausible explanation of how chronic stress may lead to a variety of human conditions and disorders, which range from merely cosmetic, like graying hair, to life-threatening disorders like malignancies," Lefkowitz said.
P53 is a tumor suppressor protein and is considered a "guardian of the genome" – one that prevents genomic abnormalities.
"The study showed that chronic stress leads to prolonged lowering of p53 levels," said Makoto Hara, Ph.D., a postdoctoral fellow in the Lefkowitz laboratory. "We hypothesize that this is the reason for the chromosomal irregularities we found in these chronically stressed mice."
Lefkowitz earlier had proved the existence of isolated, and characterized the G-protein-coupled receptors (GPCRs) such as the beta adrenergic receptor. These receptors, which are located on the surface of the membranes that surround cells, are the targets of almost half of the drugs on the market today, including beta blockers for heart disease, antihistamines and ulcer medications.
Now he is continuing studies along another pathway,stemming from the GPCRs, that was discovered in his lab, which is known as the beta-arrestin pathway. At first, the theory was that beta-arrestin proteins turned off or desensitized the G-protein pathways, but evidence is accumulating that these proteins are also responsible for causing certain biochemical activities in their own right.
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.
Other authors include Jeffrey J. Kovacs, Erin J. Whalen, Sudarshan Rajagopal, Ryan T. Strachan, Seungkirl Ahn, Barbara Williams, Christopher M. Lam, Kunhong Xiao, and Sudha K. Shenoy, all of the Duke Department of Medicine; Aaron J. Towers and Simon G. Gregory of the Department of Medicine and the Center for Human Genetics at Duke; and Wayne Grant and Derek R. Duckett of the Translational Research Institute, The Scripps Research Institute, Jupiter, Fla..
The study was supported by the Howard Hughes Medical Institute.
Mary Jane Gore | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy