Scripps Research Scientists Help Pinpoint Cause of Stress-Related DNA Damage

August 23, 2011

Working closely with a team of researchers from Duke University, scientists from the Florida 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.

The new findings, published in the journal Nature on August 21, 2011, could not only explain the development of certain human disorders, they could also offer a potential model for prevention and therapy.

While the human mind and body are built to respond to stress-the well-known "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 in turn can result in various neuropsychiatric conditions, miscarriages, cancer, and even aging itself.

Until the new study, however, exactly how chronic stress wreaks havoc on DNA was basically unknown.

"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 β-arrestin-1 as an important player."

The long-term effects of these stress hormones on DNA damage identified in the study represent a conceptual as well as a tangible advance, according to Robert J. Lefkowitz, a Duke University professor of medicine who led the study.

Since stress is not time-limited and can be sustained over months or even years, it is well appreciated that persistent stress may have adverse effects for the individual. These new findings not only uncover a novel pathway, but also have important practical implications.

"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," Leftkowitz said. "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."

A Newly Discovered Mechanism

The newly uncovered mechanism involves β-arrestin-1proteins, 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.

The first author of the study, "Stress Response Pathway Regulates DNA Damage through β2-Adrenoreceptors and β-Arrestin-1," is Makoto R. Hara of Duke University. In addition to Duckett and Hara, other authors include Jeffrey J. Kovacs, Erin J. Whalen, Sudarshan Rajagopal, Ryan T. Strachan, Aaron J. Towers, Barbara Williams, Christopher M. Lam, Kunhong Xiao, Sudha K. Shenoy, Simon G. Gregory, Seungkirl Ahn, and Robert J. Lefkowitz of Duke University; and Wayne Grant of Scripps Research.

The study was supported by the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.

The Scripps Research Institute

---

---

	The Chemical Biology of DNA Damage by Nicholas E. Geacintov (Editor), Suse Broyde (Editor) Bringing the power of biochemical analysis to toxicology, this modern reference explains genotoxicity at the molecular level, showing the links between a DNA lesion and the resulting cellular or organismic response. Clearly divided into two main sections, Part 1 focuses on selected examples of important DNA lesions and their biological impact, while the second part covers current advances in assessing and predicting the genotoxic effects of chemicals, taking into account the biological responses mediated by the DNA repair, replication and transcription machineries. A ready reference for biochemists, toxicologists, molecular and cell biologists, and geneticists seeking a better understanding of the impact of chemicals on human health.
	DNA Damage and Repair: Volume III: Advances from Phage to Humans (Contemporary Cancer Research) by Jac A. Nickoloff (Editor), Merl F. Hoekstra (Editor) Jac A. Nickoloff and Merl F. Hoekstra update and expand their two earlier acclaimed volumes (Vol. I: DNA Repair in Prokaryotes and Lower Eukaryotes and Vol. II: DNA Repair in Higher Eurkaryotes) with cutting-edge reviews by leading authorities of primary experimental findings about DNA repair processes in cancer biology. The reviews cover a wide range of topics from viruses and prokaryotes to higher eukaryotes, and include several new topics, among them the role of recombination in replication of damaged DNA, X-ray crystallographic analysis of DNA repair protein structures, DNA repair proteins and teleomere function, and the roles of BRCA1 and BRCA2 in DNA repair. Authoritative and up-to-date, DNA Damage and Repair, Vol. III: Advances from Phage to Humans surveys the rapidly moving...
	Oxidative DNA damage estimated by urinary 8-hydroxydeoxyguanosine and indoor air pollution among non-smoking office employees [An article from: Environmental Research] by C.Y. Lu (Author), Y.C. Ma (Author), J.M. Lin (Author), C.Y. Chuang (Author), F.C Sung (Author) This digital document is a journal article from Environmental Research, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: This study investigated whether urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of oxidative stress, was associated with indoor air quality for non-smokers in high-rise building offices. With informed consents, urine samples from 344 non-smoking employees in 86 offices were collected to determine 8-OHdG concentrations. The concentrations of carbon dioxide (CO"2) and total volatile organic compounds (TVOCs) in each office and outside of the building were simultaneously measured for eight office hours. The...
	DNA Damage and Repair: Volume II: DNA Repair in Higher Eukaryotes (Contemporary Cancer Research) by Jac A. Nickoloff (Editor), Merl F. Hoekstra (Editor) Cutting edge reviews by leading researchers illuminate key aspects of DNA repair in mammalian systems and its relationship to human genetic disease and cancer. Major topics include UV and X-Ray repair, repair of chemical damage, recombinational repair, mismatch repair, transcription-repair coupling, and the role of DNA repair in disease prevention. Extensive up-to-date references and rigorous peer-review of each chapter make this volume definitive and bring it to the active frontiers of research.
	Deoxyribonucleic acid (DNA) biosensors for environmental risk assessment and drug studies [An article from: Analytica Chimica Acta] by G. Bagni (Author), D. Osella (Author), E. Sturchio (Author), M. Mascini (Author) This digital document is a journal article from Analytica Chimica Acta, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: In the present work, electrochemical DNA biosensors are proposed as a screening device for the rapid bio-analysis of environmental pollution and DNA-drug interaction studies. The binding of small molecules to DNA immobilised on disposable screen-printed electrodes has been measured through the variation of the electrochemical signal of guanine by square wave voltammetric scans. These kinds of biosensors were used to evaluate the soil contamination level in an Italian polluted area and the results were compared...
	In Situ Detection of DNA Damage: Methods and Protocols (Methods in Molecular Biology) by Vladimir V. Didenko (Editor) In In Situ Detection of DNA Damage: Methods and Protocols, Vladimir Didenko and a panel of experts describe all the major in situ techniques for studying DNA damage and apoptosis, and how approaches originally designed to label apoptotic cells can be used for DNA damage analysis (and vice versa). The readily reproducible techniques presented here include all those designed to detect specific single- and double-stranded DNA breaks in tissue sections while using polymerases, ligases, nucleases, and kinases. There are also novel instrumental techniques that use ultrasound for in vivo and in situ detection of apoptotic DNA damage, and in situ applications of flow and laser-scanning cytometry for analysis of DNA strand breaks and apoptosis. State-of-the-art and highly practical, In Situ...
	Structural Biology of DNA Damage and Repair (ACS Symposium) by Michael Stone (Editor) The human genome is continuously exposed to many classes of genotoxins. Of these, three that will be discussed herein include 5,6-dihydroxy-5,6- dihydrothymine (thymine glycol; Tg), O6-methylguanine (O6MeG), and benzo[a]pyrene. In all cases, if the genome is not repaired, these and other genotoxic lesions precipitate serious biological consequences, including altered gene expression, mutation, and cell death. In addition to the genotoxic responses, it is increasingly being recognized that DNA lesions can alter the epigenetic profiles that are imprinted by naturally occurring DNA modifications. The impetus for this volume came from a recent symposium sponsored by the ACS Division of Chemical Toxicology, bringing together scientists interested in the synthesis and structures of...
	Chemoprevention of Cancer and DNA Damage by Dietary Factors by Siegfried Knasmüller (Editor), David M. DeMarini (Editor), Ian Johnson (Editor), Clarissa Gerhäuser (Editor) This reference work provides a comprehensive overview of the field of dietary chemoprevention of cancer. It reviews the wide variety of dietary factors and mechanisms of anticarcinogenesis and antimutagenesis that have been identified in vitro and in animal and human studies. This volume covers the most recent molecular mechanism by which dietary antimutagens and anticarcinogens function, and also notes the needs for further research in this potentially important area of public health. It is a must-have reference for nutritional scientists, medicinal chemists, food scientists, biotechnologists, pharmacists, and molecular biologists working in academia or the pharmaceutical and food industries, as well as governmental and regulatory agencies concerned with nutrition and cancer. With a...
	DNA Damage Recognition by Wolfram Siede (Editor), Paul W. Doetsch (Editor) Stands as the most comprehensive guide to the subject—covering every essential topic related to DNA damage identification and repair. Covering a wide array of topics from bacteria to human cells, this book summarizes recent developments in DNA damage repair and recognition while providing timely reviews on the molecular mechanisms employed by cells to distinguish between damaged and undamaged sites and stimulate the appropriate repair pathways. about the editors... WOLFRAM SIEDE is Associate Professor, Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth.  He received the Ph.D. degree (1986) from Johann Wolfgang Goethe University, Frankfurt Germany. YOKE WAH KOW is Professor, Department of Radiation Oncology, Emory University...
	The DNA Damage Response: Implications on Cancer Formation and Treatment by Kum Kum Khanna (Editor), Yosef Shiloh (Editor) The book The DNA Damage Response: Implications on Cancer Formation and Treatment brings together a great collection of review articles. The articles have been written by a group of experts who have a deep knowledge of the recent advances in the fields of DNA damage signalling and repair and their implications in carcinogenesis. The book is divided into chapters that deal with the elaborate surveillance system and repair mechanisms used by cells to suppress mutagenic lesions to avoid cancer. It provides snapshots of: * current understanding of DNA damage signalling, * cell cycle checkpoints, * some of the major DNA repair pathways, * functional links between DNA damage, * genomic instability and cancer, * implications of DNA damage for the development of new...