Now scientists at the University of California, San Diego Branch of the Ludwig Institute for Cancer Research (LICR) have identified a key network of DNA repair and cell cycle control genes in yeast that prevents the deleterious effects of ROS.

"DNA repair and cell cycle control mechanisms are important guardians against cancerous changes in human cells," says Dr. Richard Kolodner, LICR Member and senior author of the study. "However, the effects of ROS on these cellular responses have not been well characterized. We've now identified a group of genes that cooperate to suppress DNA mutations and the genome rearrangements that are the hallmarks of cancer cells that occur in response to ROS."

Dr. Kolodner and lead author, Meng-Er Huang, generated various yeast strains each with a mutation in the TSA1 gene, which results in increased production of ROS, plus a mutation in one or more genes involved in DNA repair or cell cycle control. Cell survival and accumulation of DNA mutations and gross chromosomal rearrangements in each strain were then analysed to identify genes that cooperate to prevent the deleterious effects of ROS and promote normal cell survival.

"These results suggest that endogenous ROS-induced genome instability may contribute to cancer progression," says Dr. Kolodner, professor of medicine with UCSD School of Medicine and member of the Rebecca and John Moores UCSD Cancer Center. "And increased ROS is almost certainly more harmful in cells with acquired mutations in other genes in the network. However the connections we've found might point to new strategies, like dietary supplements, that will alleviate some of the clinical symptoms of human diseases associated with genetic deficiencies of DNA damage responses."

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Physicians and researchers have long been puzzled by the discrepancy between the large numbers of people with brain aneurysms -- 10 to 15 million people in the U.S. -- and the incidence of aneurysms rupturing in a relatively small fraction of those people. Doctors knew some aneurysms were more prone to rupture, but didn't know why. They suspected genes played a role, but lacked convincing studies supporting this hypothesis.

The Mayo Clinic research team had previously done extensive work with a molecule (nitric oxide synthase) known to play a pivotal role in the endothelium. The endothelium is the lining of the blood vessels that is very important to maintaining smooth blood flow. Disrupted blood flow in brain arteries is associated with increased risk of stroke. The Mayo team's previous work showed that when the amount of this molecule is increased using a gene therapy approach, the arteries relax and maintain smooth, healthy flow.

To determine the role of nitric oxide synthase gene variations in ruptured brain aneurysms, the Mayo Clinic team screened the genetic variants of 49 patients who had unruptured brain aneurysms, and compared them with the genetic variants of 58 emergency room patients with ruptured aneurysms.

Blood samples were taken from all, and DNA analysis performed. There was no significant difference between the two groups in terms of age, race, gender, health history, family history, and smoking habits. Despite these similarities, the genetic differences were striking. Says Dr. Khurana: "Our findings are the first to present strong evidence that the reason for sporadic brain aneurysm rupture may be genetic."

In addition to Dr. Khurana, other Mayo Clinic collaborators include: Irene Meissner, M.D.; Youvraj Sohni, Ph.D.; William Bamlet; Robyn McClelland, Ph.D.; Julie Cunningham, Ph.D.; and Fredric Meyer, M.D. Their work was supported by the Departments of Neurologic Surgery and Neurology, Mayo Clinic and Mayo Foundation.

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