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Raising the alarm when DNA goes bad
August 14, 2009Our genome is constantly under attack from things like UV light and toxins, which can damage or even break DNA strands and ultimately lead to cancer and other diseases. Scientists have known for a long time that when DNA is damaged, a key enzyme sets off a cellular 'alarm bell' to alert the cell to start the repair process, but until recently little was known about how the cell detects and responds to this alarm. In a study published today in Nature Structural and Molecular Biology, researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have identified a whole family of proteins capable of a direct response to the alarm signal.
Our genome is a huge repository of information guiding the construction and function of all the cells in our bodies. Cells sustain many hits to their DNA every day, which can lead tomutations, so they maintain a fleet of DNA repair machinery that can be rapidly mobilised and sent to damaged sites in an emergency.
What these proteins share is a special region called a macrodomain. By using a laser to reproduce DNA damage in the lab, the scientists were able to follow fluorescently-labelled macrodomain proteins in cells and observed that they quickly move to the site of DNA damage. A high-resolution image, obtained by X-ray crystallography, shows how the macrodomain forms a 'pocket' fitting the PAR signal exactly.
Among the members of the family the researchers found a protein called histone macroH2A1.1. "This was very surprising. Histones play a major role in assembling chromatin and keeping it together, but they don't usually have macrodomains," says Ladurner. "The finding is particularly relevant, because it turns out that cancer cells don't have macroH2A1.1. The fact that one member of the rapid response team that detects DNA damage is missing could contribute to the disease."
Because macroH2A1.1 is embedded in chromatin, when it recognises PAR at DNA damage sites, it drags the complex but highly-organised tangle of chromatin with it. As a result, macroH2A1.1 condenses the chromatin environment around the damaged area.
The scientists are now trying to understand why this happens. One plausible explanation could be that by temporarily compacting the DNA, the broken ends of the DNA molecule are kept closer together. This should increase the chances of being able to repair it.
"With these findings we've opened up completely new perspectives to a fifty-year-old field of research," says Ladurner. "We're very excited of what lies ahead and hope that we'll soon be much closer in understanding how PARP1 and macrodomains together maintain a healthy genome."
European Molecular Biology Laboratory
Chromatin Current Events and Chromatin News RSSGerton Lab determines the composition of centromeric chromatin
The Stowers Institute's Gerton Lab has provided new evidence to clarify the structure of nucleosomes containing Cse4, a centromere-specific histone protein required for proper kinetochore function, which plays a critical role in the process of mitosis. The work, conducted in yeast cells, was published in the most recent issue of Molecular Cell.
Researchers identify protein-telomere interactions that could be key in treating cancer
A team of researchers from The Wistar Institute have shown that a large non-coding RNA in mammals and yeast plays a central role in helping maintain telomeres, the tips of chromosomes that contain important genetic information and help regulate cell division.
Protein plays unexpected role protecting chromosome tips
A protein specialist that opens the genomic door for DNA repair and gene expression also turns out to be a multi-tasking workhorse that protects the tips of chromosomes and dabbles in a protein-destruction complex, a team lead by researchers at The University of Texas M. D. Anderson Cancer Center reports in the Aug. 13 edition of Molecular Cell.
Conaway Lab uncovers function of potential cancer-causing gene product
The Stowers Institute's Conaway Lab has uncovered a previously unknown function of a gene product called Amplified in Liver Cancer 1 (Alc1), which may play a role in the onset of cancer.
LincRNAs serve as genetic air-traffic controllers
Earlier this year, a scientific team from Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute identified a class of RNA genes known as large intervening non-coding RNAs or "lincRNAs," a discovery that has pushed the field forward in understanding the roles of these molecules in many biological processes, including stem cell pluripotency, cell cycle regulation, and the innate immune response.
BRIT1 allows DNA repair teams access to damaged sites
Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access.
Novel DNA vaccine leads to kidney damage prevention in systemic lupus erythematosus models
DNA vaccination using lupus autoantigens and interleukin-10 (IL-10, a cytokine that plays an important role in regulating the immune system) has potential as a novel therapy to induce antigen specific tolerance and may help to prevent kidney damage in patients with systemic lupus erythematosus (SLE).
USC researchers identify DNA mutation that occurs at beginning point of T-cell lymphoma
Researchers at the Keck School of Medicine of the University of Southern California (USC) have identified a key mechanism that causes chromosomes within blood cells to break-an occurrence that marks the first step in the development of human lymphoma.
Cocaine-linked genes enhance behavioral effects of addiction
New research sheds light on how cocaine regulates gene expression in a crucial reward region of the brain to elicit long-lasting changes in behavior.
Farnesoid X receptor regulates cystathionase
The expression and activity of Cystathionase is reduced in rodent models of liver injury, leading to hyper-homocysteinemia and impaired generation of hydrogen sulphide, two factors that contribute to endothelial dysfunction and increased intrahepatic resistance.
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