Monday, February 15, 2010

RESEARCHERS FIND NEW WAY TO STUDY HOW ENZYMES REPAIR DNA SUN DAMAGE

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Researchers at Ohio State University have found a new way to study how enzymes move as they repair DNA sun damage -- and that discovery could one day lead to new therapies for healing sunburned skin.

Ultraviolet (UV) light damages skin by causing chemical bonds to form in the wrong places along the DNA molecules in our cells. Normally, other, even smaller molecules called photolyases heal the damage. Sunburn happens when the DNA is too damaged to repair, and cells die.

Photolyases have always been hard to study, in part because they work in tiny fractions of a second. In this week’s online edition of the Proceedings of the National Academy of Sciences, Ohio State physicist and chemist Dongping Zhong and his colleagues describe how they used ultra-fast pulses of laser light to spy on a photolyase while it was healing a strand of DNA.

This is the first time that anyone has observed this enzyme motion without first attaching a fluorescent molecule to the photolyase, which disturbs its movements. They were able to see the enzyme’s motion to help the healing process as it happens in nature.

“Now that we have accurately mapped the motions of a photolyase at the site of DNA repair, we can much better understand DNA repair at the atomic scale, and we can reveal the entire repair process with unprecedented detail,” said Zhong, the Robert Smith Associate Professor of Physics, and associate professor in the departments of chemistry and biochemistry at Ohio State.

Such small motions are very hard to study. Typically, researchers deal with the problem by attaching tiny bits of fluorescent molecules to the enzymes they are trying to study. But adding an extra molecule to an enzyme such as photolyase could change how it moves.

“Once you tag it, you can’t be sure that the motions you detect are the true motions of the molecule as it would normally function,” Zhong explained.

So instead of using tags, he and his team took laser “snapshots” of a single photolyase in action in the laboratory. They mapped the shape and position of the photolyase molecule as it broke up the harmful chemical bonds in DNA caused by UV light. The whole reaction lasted only a few billionths of a second.

In nature, DNA avoids damage by converting UV rays into heat. Sunscreen lotions protect us by reflecting sunlight away from the skin, and also by dissipating UV as heat.

Sunburn happens when the DNA absorbs the UV energy instead of converting it to heat. This is due in part to the random position of the DNA molecule within our cells when the UV hits it. When the UV energy is absorbed, it triggers chemical reactions that form lesions -- errant chemical bonds -- along the DNA strand.

If photolyases are unable to completely repair the lesions, the DNA can’t replicate properly. Badly damaged cells simply die — that’s what gives sunburn its sting. Scientists also believe that chronic sun damage creates mutations that lead to diseases such as skin cancer.

The work in Zhong’s lab is fundamental to the understanding of how those molecules interact. Other researchers could use this information to design drugs to heal sun damage.

“Of course, the ultimate goal of studying DNA repair is to help design artificial systems to mimic it,” he said.

(Photo: OSU)

Ohio State University

STUDY SHOWS CIGARETTE SMOKING A RISK FOR ALZHEIMERS DISEASE

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A UCSF analysis of published studies on the relationship between Alzheimer’s disease and smoking indicates that smoking cigarettes is a significant risk factor for the disease. After controlling for study design, quality of the journals, time of publication, and tobacco industry affiliation of the authors, the UCSF research team also found an association between tobacco industry affiliation and the conclusions of individual studies. Industry-affiliated studies indicated that smoking protects against the development of AD, while independent studies showed that smoking increased the risk of developing the disease.

Study findings were published online in the January issue (19:2) of the Journal of Alzheimer’s Disease.

“For many years, published studies and popular media have perpetuated the myth that smoking is protective against the development of AD. The disease’s impact on quality of life and health care costs continues to rise. It is therefore critical that we better understand its causes, in particular, the role of cigarette smoking,” said Janine K. Cataldo, PhD, RN, assistant professor in the UCSF School of Nursing and lead author of the study.

According to the Alzheimer’s Association, 5.3 million Americans currently have the disease, and that number will escalate rapidly as the baby boom generation ages. AD also triples health care costs for Americans aged 65 and older, the organization states.
The UCSF team reviewed 43 published studies from 1984 to 2007. Authors of one-fourth of the studies had an affiliation with the tobacco industry.

The UCSF team determined that the average risk of a smoker developing AD, based on studies without tobacco industry affiliation, was estimated to be 1.72, meaning that smoking nearly doubled the risk of AD. In contrast, the team found that studies authored by individuals with tobacco industry affiliations, showed a risk factor of .86 (less than one), suggesting that smoking protects against AD. When all studies were considered together, the risk factor for developing AD from smoking was essentially neutral at a statistically insignificant 1.05.

Previous reviews of the association between smoking and AD have not controlled for study design and author affiliation with the tobacco industry, according to Cataldo. To determine if study authors had connections to the tobacco industry, the UCSF team analyzed 877 previously secret tobacco industry documents.

The researchers used an inclusive definition of “tobacco industry affiliation” and examined authors’ current or past funding, employment, paid consultation, and collaboration or co-authorship on a study with someone who had current or previous tobacco industry funding within 10 years of publication.

“We know that industry-sponsored research is more likely to reach conclusions favorable to the sponsor,” said Stanton A. Glantz, PhD, of the UCSF Department of Medicine and a study co-author. “Our findings point to the ongoing corrosive nature of tobacco industry funding and point to the need for academic institutions to decline tobacco industry funding to protect the research process.”

(Photo: UCSF)

The University of California, San Francisco

BAD NEWS FOR MOSQUITOES: YALE STUDY MAY LEAD TO BETTER TRAPS, REPELLENTS

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Yale University researchers have found more than two dozen scent receptors in malaria-transmitting mosquitoes that detect compounds in human sweat, a finding that may help scientists to develop new ways to combat a disease that kills 1 million people annually.

These olfactory receptors in the mosquito Anopheles gambiae offer scientists potential new targets for repelling, confusing or attracting into traps the mosquitoes that spread a disease afflicting up to 500 million people across a broad swath of the world’s tropical regions, according to authors of the article published online Feb. 3 in the journal Nature.

“The world desperately needs new ways of controlling these mosquitoes, ways that are effective, inexpensive, and environmentally friendly,” said John Carlson, the Eugene Higgins Professor of Molecular, Cellular, and Developmental Biology at Yale and senior author of the study. “Some of these receptors could be excellent targets for controlling mosquito behavior.”

While it has long been known that mosquitoes are attracted to human scents, just how the mosquito’s olfactory system detects the different chemical elements of human odor has been unknown.

“Mosquitoes find us through their sense of smell, but we know very little about how they do this,” Carlson said. “Here in the United States, mosquitoes are a source of annoyance, but in much of the world they’re a source of death.”

Carlson’s lab identified the first insect odor receptors in 1999 in studies of the fruit fly. The Yale team then found an ingenious way to use the fruit fly to study how the mosquito olfactory system works: They used mutant flies that were missing an odor receptor. Under the leadership of Allison Carey, an M.D./Ph.D. candidate in Carlson’s lab and lead author of the study, the researchers systematically activated genes of 72 mosquito odor receptors in fruit fly olfactory cells that lacked their own receptors. The engineered flies were then exposed to a battery of scent compounds, and the responses conferred by each receptor were analyzed. Over the course of the project, Carey recorded 27,000 electrical responses in the genetically engineered fly/mosquito olfactory system to the library of scents.

Particularly strong responses were recorded from 27 receptors – and most of these receptors responded to chemical compounds found in human sweat.

“We’re now screening for compounds that interact with these receptors,” Carlson said. “Compounds that jam these receptors could impair the ability of mosquitoes to find us. Compounds that excite some of these receptors could help lure mosquitoes into traps or repel them. The best lures or repellents may be cocktails of multiple compounds.”

Carey says that more knowledge about mosquito behavior and odor reception will help develop more effective traps and repellents.

(Photo: Yale U.)

Yale University

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