In research published in the March 17 online edition of the journal PLoS Genetics, Tufts University biologist Catherine Freudenreich, and then-graduate student Rangapriya Sundararajan show that cell death in yeast can also result from the process by which the cell repairs damage that occurs within a repeated CAG/CTG sequence.
The findings provide additional insight into the causes of some neurodegenerative diseases. "This represents a new way in which the expanded repeats may be causing cell death that leads to the disease," says Freudenreich. , associate professor of biology at the School of Arts and Sciences at Tufts University "The expanded DNA in and of itself can be toxic to cells."
Scientists have observed that Huntington's disease, myotonic dystrophy and multiple subtypes of spinal cerebella ataxia are caused when the number of repeats at the disease locus exceeds a stability threshold. For Huntington's disease, the threshold is 38 to 40 repeats. Myotonic dystrophy results when there are close to 200 repeats.
When these expanded repeats occur, the abnormal DNA is copied faithfully into ribonucleic acid, the chemical cousin of DNA. In myotonic dystrophy the errant RNA has a toxic effect because it grabs onto and holds hostage certain proteins, preventing them from carrying out the myriad functions that are vital to the cell.
In Huntington’s disease and the ataxias, the RNA serves as a blueprint for an abnormal protein that contains an excessive amount of an amino acid called glutamine.
In her experiment, Freudenreich found a cause of cell death that arises from a DNA checkpoint response. She started with a piece of human DNA that was cloned from a myotonic dystrophy patient. It contained CAG/CTG repeats of 70 and 155. She then placed the tract within a yeast chromosome.
Multiple types of DNA damage can occur at an expanded trinucleotide repeat. Damage of this magnitude triggers checkpoint proteins that respond like genomic firefighters to the emergency. In normal circumstances these proteins halt the cell growth cycle until the damage is repaired.
In Freudenreich's study, the cell damage activated the Rad53 checkpoint kinase. But here, the protein arrested cell growth for an abnormally long period of time without repairing the damage.
This often resulted in cell death. In cases where the cell did manage to recover and keep dividing, the researchers observed an increased frequency of repeat expansions.
"The cells that were having trouble growing and dividing due to the expanded repeat accumulated additional expansions. It became a vicious loop." says Freudenreich. She adds, "It will be important in the future to determine if this phenomenon is contributing to the cell death that causes the human diseases."
Myotonic dystrophy is an inherited condition that affects muscles and other body systems. It is the most common form of adult onset muscular dystrophy, with progressive muscle wasting as well as a variety of other symptoms.
Huntington's disease is a genetic disease involving degeneration of the central nervous system, leading to uncontrolled muscle movements, emotional instability and dementia.
Folk musician and songwriter Woody Guthrie died from complications of the disease in 1967.
Freudenreich and Sundararajan's work was funded by a National Institutes of Health grant.
Sundararajan R, Freudenreich CH (2011) Expanded CAG/CTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomyces cerevisiae. PLoS Genet 7(3): e1001339. doi:10.1371/journal.pgen.1001339
Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.
Alex Reid | Newswise Science News
Ambush in a petri dish
24.11.2017 | Friedrich-Schiller-Universität Jena
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons
The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
24.11.2017 | Physics and Astronomy
24.11.2017 | Health and Medicine
24.11.2017 | Earth Sciences