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RESEARCH BRIEFSCaretaker Protein May Moonlight as Gatekeeper—and Vice VersaMice lacking a protein that helps patch together the ends of broken chromosomes could hold the key to a mystery in biology. For years, researchers suspected that the DNA repair protein, DNA-PKcs—known as a genomic caretaker—might have other roles in the cell. It now appears that the protein may serve as a backup to one of the gatekeepers of the cell, ATM, the protein defective in the cancer-prone disease, ataxia telangiectasia, HMS researchers report in the March 13 Proceedings of the National Academy of Sciences.
Mice lacking both ATM and DNA ligase IV tend to exhibit odd chromosomal arrangements because they are lacking two proteins presumed to play a role in DNA repair. The chromosomal structure shown above consists of a single chromatid from chromsome 6 (orange) fused to a single chromatid from chromosome 8 (green). Courtesy of David Ferguson "People have looked for a functional relationship between these two proteins for a long time," said Fred Alt, the Charles A. Janeway professor of pediatrics. "This is the first evidence that would relate these two activities—the caretaking and the gatekeeping." JoAnn Sekiguchi, research fellow in genetics, and David Ferguson, instructor in pathology, are first authors on the paper. To uncover the novel DNA-PKcs function, the researchers created mice lacking both the ATM and DNA-PKcs genes. Normally, mice lacking just DNA-PKcs survive quite well, and mice lacking ATM are small and susceptible to lymphomas. But the double knockouts died long before birth. "If ATM and DNA-PKcs have overlapping or related functions, eliminating them both might cause the early death," said Ferguson. Mice lacking another caretaker protein in the same repair pathway as DNA-PKcs, DNA ligase IV, typically die in utero. But, intriguingly, when the researchers knocked out the ATM gene from the ligase IV–deficient mice, the double mutants survived past birth. Why were the mice rescued? When a cell's DNA is damaged, one of the primary jobs of ATM is to detect the damage and signal another protein, p53, to stop the cell from dividing. But lacking ATM, ligase IV–deficient cells, which accumulate unrepaired DNA damage, could escape detection and proliferate. There is another twist to the story. Although the ligase IV–ATM double mutants survived past birth, they died soon afterwards. Yet previous experiments by Alt and his colleagues had shown that mice lacking ligase IV and p53 could live for months. Curiously, the lack of the p53 gatekeeper did not increase genomic instability in ligase IV–deficient cells, as opposed to ATM deficiency, which increased the chromosomal damage (see image). The high level of DNA damage likely led to the rapid postnatal demise of the ligase IV-ATM mutants. These studies highlight the complex interplay between genomic caretakers and cellular gatekeepers. ATM is at the crossroads of these functions, said Ferguson. Pilot Study Suggests Ischemic Stroke TriggersOnce every 53 seconds, someone in the U.S. suffers a stroke. About 25 percent of these victims die within a year, making stroke the third leading cause of death after heart disease and cancer. In addition, recovery for those lucky to survive is often slow and incomplete, leaving many stroke victims in need of permanent care. While much is known about the risk factors that increase one's susceptibility to an acute ischemic stroke, little is known about the immediate triggers of these events. This may be about to change. In the Stroke Onset Pilot Study, reported in the January Stroke, Murray Mittleman, assistant professor of medicine at Beth Israel Deaconess Medical Center, and colleagues identified potential stroke triggers among a group of 50 sufferers. The patients, interviewed within two to three days of an ischemic stroke episode, were able to identify behaviors that may have precipitated their attacks. Alcohol consumption was most common, followed by the lifting of heavy objects, strenuous physical exertion, marijuana use, outbursts of anger, straining one's self while urinating or defecating, and sexual intercourse. The success of the pilot study, which was based on an epidemiological method that used each patient as his or her own control, prepares the way for a larger study to determine if these external factors are critical for stroke onset. This, in turn, may lead to new strategies for prevention. —Thomas Fagan Medicare Patients Give Higher Overall Marks to Nonprofit than For-profit Health PlansWhen it comes to the overall experience with their health plan, Medicare patients rate for-profit and nationally affiliated managed health care plans much lower than not-for-profit or local plans, according to a recent study by Harvard researchers. This is the first large scale national study that examines the relationship between health plan characteristics and patient ratings of their plan rather than the technical quality of their medical care. Patients in for-profit and nationally affiliated health plans, for example, report more problems in their dealings with the health plan and in their ability to obtain needed services and equipment. There were few differences, however, in patient ratings of their physician, suggesting that patients were able to dis-tinguish between the care they receive from their physician and the services they receive from their plan. The study appears in the March/April Health Affairs. "On the whole, for-profit health plans were rated significantly worse, though some individual for-profit health plans still performed well," said lead author and HMS instructor in health care policy Bruce Landon. These results are consistent with the growing number of other studies that have shown poorer performance in some aspects of care by for-profit health care. "These types of assessments of patient experiences with health care that distinguish between different health plans or health plan types could become increasingly important for contracting and enrollment decisions, counterbalancing the focus on costs that traditionally has driven most enrollment and purchasing decisions." The results of this study were generated by linking data from the federally funded Medicare implementation of the Consumer Assessments of Health Plans Survey (CAHPS), a standardized survey developed at HMS and administered nationwide to Medicare patients, with data from the InterStudy Competitive Edge database, which catalogues health plan characteristics. In total, the researchers based their conclusions on CAHPS survey responses from more than 82,000 Medicare patients from 182 health plans nationwide. —Heather Ettinger Report Gives Guidelines for Raising TeensThe teenage years are some of the most trying and puzzling for parents and others responsible for nurturing teens, and conflicting messages abound on how to cope with these challenges. A new report by the Center for Health Communication at HSPH, written for the media, policymakers, and practitioners, as well as parents, aims to cut through the confusion. Raising Teens: A Synthesis of Research and a Foundation for Action, distills findings from more than 300 studies into key messages about raising teenagers on which there is widespread agreement among researchers and practitioners. The 96-page report is organized around the "10 tasks of adolescence"—developmental demands related to identity, cognition, emotional expression, values, sexuality, roles, and relationships—whose fulfillment parents and caregivers can support or, in unfortunate cases, thwart. A key theme is the importance of staying involved in teenagers' lives, even when they seem to reject and resent that involvement. Parental roles are summarized in "five basics of parenting adolescents," and for each of these—love and connect, monitor and observe, guide and limit, model and consult, and provide and advocate—specific strategies for how to effectively perform the role are offered. The report is authored by A. Rae Simpson, chief consultant to the center and administrator of parenting programs at MIT. It is a product of the Project on the Parenting of Adolescents, with Jay Winsten, associate dean for public and community affairs at HSPH, as principal investigator and with support from the John D. and Catherine T. MacArthur Foundation. "The hope is that the added information will have a ripple effect," Simpson writes, "serving as a tool for the collective efforts of teens, parents, families, the media, schools, communities, professional groups, religious leaders, and policymakers in building better supports for the next generation." |
