January 28, 2010

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.

More information: http://www.pnas.org/

Provided by The Ohio State University (news : web)

DNAWellnessinfo.com Resource:  http://www.physorg.com/news183913344.html

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ScienceDaily (Jan. 14, 2010) — Researchers at the University of Minnesota have discovered a molecular security system in human cells that deactivates and degrades foreign DNA. This discovery could open the door to major improvements in genetic engineering and gene therapy technologies.

Led by Reuben Harris, associate professor of biochemistry, molecular biology and biophysics in the College of Biological Sciences, the report’s findings will be published online by Nature Structural and Molecular Biology on Jan. 10.

In the study, Harris and colleagues show how APOBEC3A, an enzyme found in human immune cells, disables double-stranded foreign DNA by changing cytosines (one of the four main bases in DNA) to uracils (an atypical DNA base). Persisting DNA uracils result in mutations that disable the DNA. In addition, the authors show that other enzymes step in to degrade the uracil-containing foreign DNA and sweep its remains out of the cell.

“Scientists have known for a long time that some human cells take up DNA better than others, but we haven’t had good molecular explanations,” Harris says. “This is definitely one of the reasons. Foreign DNA restriction is a fundamental process that could have broad implications for a variety of genetic diseases.”

By understanding how the mechanism works, scientists can develop ways to manipulate it to enable more effective methods to swap bad genes for good ones. Harris is also intrigued to learn why the mechanism doesn’t affect a cell’s own DNA.

The discovery of an analogous foreign DNA restriction mechanism in bacteria launched the field of genetic engineering during the 1970s. Once bacterial DNA restriction enzymes were understood, their power was harnessed to cut and paste segments of DNA for a wide variety of therapeutic and industrial purposes.

DNAWellnessinfo.com Resource:  http://www.sciencedaily.com/releases/2010/01/100110151321.htm

Molecular Security System That Protects Cells from Potentially Harmful DNA Discovered is a post from: dnawellnessinfo.com

ScienceDaily (Jan. 1, 2010) — In the harsh judgment of natural selection, the ultimate measure of success is reproduction. So it’s no surprise that life spends lavish resources on this feat, whether in the courtship behavior of birds and bees or replicating the cells that keep them alive. Now research has identified a new piece in an elaborate system to help guarantee fidelity in the reproduction of cells, preventing potentially lethal mutations in the process.

n experiments to be published in the December 18 issue of the Journal of Biological Chemistry, researchers at The Rockefeller University identified the molecule SMARCAL1 as part of cells’ damage control response to malfunctioning DNA replication. In typical cell division, many different molecules have roles in guaranteeing the daughter strands of DNA are as identical as possible to their parent. Some molecules check for errors or ‘proofread’ the offspring for typos, for instance; others, when alerted to a problem, arrest the replication process and conduct repairs.

Lisa Postow, a postdoctoral fellow in Hironori Funabiki’s Laboratory of Chromosome and Cell Biology, used mass spectroscopy to identify SMARCAL1 as involved in this intricate quality control process. Working with Brian T. Chait’s Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, Postow found the protein in a proteomics screen for molecules that were drawn to a dangerous DNA repair problem called a double-strand break.

In both human cells and in cells from African clawed frog egg extract, Postow found that at double-strand breaks, SMARCAL1 gathered with another molecule called RPA, which is known to coat broken strands of DNA and protect them while damage is repaired. SMARCAL1 had an added interest, too: A mutation in the gene that produces it is involved in a rare but lethal disease called Schimke immuno-osseous dysplasia, a disorder that causes wide-ranging problems including kidney malfunction, immunodeficiency and growth inhibition.

To Postow’s surprise, she found that removing SMARCAL1 had little effect on double-strand break repair. However, it did facilitate a different aspect of the DNA damage response called replication fork stabilization, a process that holds steady the junction between parental and daughter strands — the replication fork — when replication is stalled because a problem has been detected. “For a mutation that causes such wide-ranging and severe physiological effects, it is surprising that the protein has such a relatively small effect at the cellular level,” Postow says.

Postow’s findings were largely corroborated by independent new research into SMARCAL1, which was published this fall in four back-to-back papers in Genes & Development. The work reveals another piece of the complex safeguards the body has in place to protect against dangerous mutations.

“This study also proves that the proteomic approach that Lisa has developed with Dr. Chait can efficiently identify proteins involving the DNA-damage recognition and repair process,” says Funabiki. “Many more excitements are ahead of us.”

DNAWellnessinfo.com Resource:  http://www.sciencedaily.com/releases/2009/12/091231152519.htm

New Molecule Identified in DNA Damage Response is a post from: dnawellnessinfo.com

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