慢性应激引起DNA损伤机理
作者：程凤 来源：科技日报 发布时间：2011-8-30过去数年，研究人员虽一直将慢性应激与染色体损伤联系起来，但直至近日，研究人员才发现慢性应激导致染色体损伤的原因。据美国物理学家组织网报道，杜克大学医学中心的研究人员首次发现了一个明确的机制，从DNA（脱氧核糖核酸）损伤的角度解释应激反应。
慢性应激的一个标志即肾上腺素升高。罗伯特·J·莱夫科维茨以前已证明了孤立的G蛋白偶联受体（GPCPs）如β肾上腺素受体的存在。这些环绕于细胞周围的细胞膜表面的受体，是目前市场上几乎一半药物的靶点，包括心脏病、抗组胺药和溃疡药物的β-受体阻滞剂。
现在，他对一种源于GPCRs的通路，即在实验室里发现的β抑制蛋白通路继续进行研究。研究人员最初以为是β抑制蛋白通路使G蛋白通路关闭或丧失敏感性，但是越来越多证据表明，这些蛋白质在行使自己权利时也会导致某些生物化学活动。在目前的研究中，科学家们发现了一种分子机制。通过该机制，类似肾上腺素的化合物通过G蛋白和β抑制蛋白通路行动而引发DNA损伤。
在这项研究中，小鼠被通过一种β肾上腺素受体注入了类似肾上腺素的化合物，出现了P53的退化，并且这种退化会随着时间的推移而加剧。而P53是一种肿瘤抑制蛋白，被看做是“基因的保护者”，能够防止基因组异常。研究者称：“这项研究表明，慢性压力会导致P53的长期降低。据猜测，这就是造成我们在受慢性应激的小鼠体内发现的染色体不规则性的原因。”
研究者还发现，在缺少β抑制蛋白1的小鼠体内，DNA损伤能够被阻止。β抑制蛋白1的缺失使P53在胸腺和睾丸的细胞水平稳定化。而胸腺是对急性或慢性压力能强烈反应的器官，父亲的压力会通过睾丸影响后代的基因组。
“这使我们对慢性应激如何导致小到仅表面变化如头发花白、大至危及生命的疾病如恶性肿瘤等各种人类状况和紊乱，提供一个似乎合理的解释。”莱夫科维茨称。
[b]At last, a reason why stress causes DNA damage[/b]
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.
"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.
More information: 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.
Provided by Duke University Medical Center
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