(Press-News.org) HEIDELBERG, 12 March 2013 – Attaching chains of the small molecule ADP-ribose to proteins is important for a cell's survival and the repair of DNA damage, making this process a promising target for the development of new cancer drugs. Researchers have now identified a much sought after enzyme that removes such ADP-ribose modifications from proteins by studying a genetic mutation that causes neurodegenerative disease in humans. These findings, published today in The EMBO Journal, suggest that not only addition but also removal of ADP-ribose from proteins is essential for normal cell function.
Poly(ADP-ribose) chains have key roles in the repair of cellular DNA damage, as well as in the control of gene expression and cell death. Pharmacological drugs called PARP inhibitors prevent the addition of ADP-ribose or ADP-ribose polymers to proteins. Several of these drugs are undergoing clinical trials for the treatment of different types of cancers.
EMBO Young Investigator Ivan Ahel, a group leader at the Paterson Institute for Cancer Research at the University of Manchester, has been studying the underlying molecular processes, including an enzyme that shortens such chains piece by piece. "An enzyme that could completely uncouple ADP-ribose from proteins has remained elusive, even though such a cellular activity has been known to exist for more than 30 years," commented Ahel. "Our approach has been to combine clinical, biochemical and structural studies to see if we could pin point this enzyme activity in humans."
The eventual breakthrough came when Ahel and his collaborators Scott Williams (National Institutes of Health, USA), Gyula Timinszky and Andreas Ladurner (both from Ludwig Maximilians University Munich) teamed up with a group of clinical geneticists lead by Reza Sharifi at the Human Genetics Research Center at St George's University of London. "By studying genetic mutations in a group of patients with severe neurodegenerative disease, we found a gene that was mutated in a family that had several cases of severe progressive neurodegenerative and seizure disorder," remarked Sharifi. The product of this gene, which was named TARG1 (for terminal ADP-ribose protein glycohydrolase), exhibited the long-sought-after enzyme activity that fully removes ADP-ribose from proteins, and was further required for the proliferation of cells and response to DNA damage.
The researchers note that further work is needed to investigate the exact cellular processes where TARG exerts its functions, and to understand in more detail why mutation of this gene causes neurodegenerative disease. "Our discovery suggests a new pathogenic mechanism that may operate in a wider range of neurodegenerative disorders, the genetics of which generally remain very poorly understood," concluded Sharifi.
###
Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease
Reza Sharifi, Rosa Morra, C. Denise Appel, Michael Tallis, Barry Chioza, Gytis Jankevicius, Michael A. Simpson, Ivan Matic, Ege Ozkan, Barbara Golia, Matthew J. Schellenberg, Ria Weston, Jason G. Williams, Marianna N. Rossi, Hamid Galehdari, Juno Krahn, Alexander Wan, Richard C. Trembath, Andrew H. Crosby, Dragana Ahel, Ron Hay, Andreas G. Ladurner, Gyula Timinszky, R. Scott Williams, Ivan Ahel
Read the paper:
http://www.nature.com/emboj/journal/vaop/ncurrent/full/emboj201351a.html
doi: 10.1038/emboj.2013.51
Further information on The EMBO Journal is available at http://www.nature.com/emboj
Media Contacts
Barry Whyte
Head | Public Relations and Communications
barry.whyte@embo.org
Hartmut Vodermaier
Senior Editor, The EMBO Journal
Tel: +49 6221 8891 401
hartmut.vodermaier@embo.org
About EMBO
EMBO is an organization of more than 1500 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work.
EMBO helps young scientists to advance their research, promote their international reputations and ensure their mobility. Courses, workshops, conferences and scientific journals disseminate the latest research and offer training in techniques to maintain high standards of excellence in research practice. EMBO helps to shape science and research policy by seeking input and feedback from our community and by following closely the trends in science in Europe.
For more information: http://www.embo.org
Hereditary neurodegeneration linked to ADP-ribose modification
2013-03-12
ELSE PRESS RELEASES FROM THIS DATE:
Extremely rare triple quasar found
2013-03-12
Pasadena, CA—For only the second time in history, a team of scientists--including Carnegie's Michele Fumagalli--have discovered an extremely rare triple quasar system. Their work is published by Monthly Notices of the Royal Astronomical Society. It is available online.
Quasars are extremely bright and powerful sources of energy that sit in the center of a galaxy, surrounding a black hole. In systems with multiple quasars, the bodies are held together by gravity and are believed to be the product of galaxies colliding.
It is very difficult to observe triplet quasar ...
Stanford researchers map out an alternative energy future for New York
2013-03-12
New York Gov. Andrew Cuomo will soon decide whether to approve hydraulic fracturing for natural gas in the state. To date, no alternative to expanded gas drilling has been proposed.
But a new study finds that it is technically and economically feasible to convert New York's all-purpose energy infrastructure to one powered by wind, water and sunlight (WWS). The plan, scheduled for publication in the journal Energy Policy, shows the way to a sustainable, inexpensive and reliable energy supply that creates local jobs and saves the state billions of dollars in pollution-related ...
Fluorescent light revealed as gauge of coral health
2013-03-12
Coral reefs not only provide the world with rich, productive ecosystems and photogenic undersea settings, they also contribute an economic boost valued at hundreds of billions of dollars. But their decline in recent years due to a variety of threats—from pollution to climate warming—has lent urgency to the search for new ways to evaluate their health.
A new study by Scripps Institution of Oceanography at UC San Diego scientists has revealed that fluorescence, the dazzling but poorly understood light produced by corals, can be an effective tool for gauging their health.
As ...
Pesticide application as potential source of noroviruses in fresh food supply chains
2013-03-12
Human norovirus (hNoV), also known as the winter vomiting bug, is one of the most common stomach bugs in the world. The virus is highly contagious, causing vomiting and diarrhea, and the number of affected cases is growing. Currently there is no cure; sufferers have to let the virus run its course for a few days.
The consumption of fresh produce is frequently associated with outbreaks of hNoV but it remains difficult to identify where in the supply chain the virus first enters production.
A new study, published in the International Journal of Food Microbiology investigated ...
Fertilizers could help tackle nutritional deficiency in African country, researchers say
2013-03-12
Enriching crops by adding a naturally-occurring soil mineral to fertilisers could potentially help to reduce disease and premature death in the African country of Malawi, researchers have said.
An international study led by academics at The University of Nottingham has shown that dietary deficiency of the mineral selenium — which plays a vital role in keeping the immune system healthy and fighting illness — is likely to be endemic among the Malawi population.
They found that most Malawi soils cannot supply enough selenium for adequate human nutrition and, in a paper ...
Friend or foe: Babies choose sides early
2013-03-12
Babies have a dark side under their cute exteriors, according to University of British Columbia-led study that finds infants as young as nine months embrace those who pick on individuals who are different from them.
While previous research has shown that babies generally prefer kind actors, the new study – published by the Association for Psychological Science – is the first to suggest that infants condone antisocial behavior when it is directed at individuals who are dissimilar.
"Our research shows that by nine months, babies are busy assessing their surroundings, ...
Babies prefer individuals who harm those that aren't like them
2013-03-12
Infants as young as nine months old prefer individuals who are nice to people like them and mean to people who aren't like them, according to a new study published in Psychological Science, a journal of the Association for Psychological Science.
In our social lives, we tend to gravitate toward people who have things in common with us, whether it's growing up in the same town, disliking the same foods, or even sharing the same birthday. And research suggests that babies evaluate people in much the same way, preferring people who like the same foods, clothes, and toys that ...
Catalysts that produce 'green' fuel
2013-03-12
The energy produced by solar panels, be it heat or electricity, has to be used right away. It is hard to store and preserve and also its transportation can be rather complicated. Creating solar cells capable of producing energy in an easily storable and transportable way, that is to say fuel, is therefore the future challenge of solar energy. For this reason the scientists at SISSA are working on a catalyst that imitates and improves what nature has been able to do for millions of years.
Plants turn solar energy into sugars, the true "green" fuel, through photosynthesis. ...
RI Hospital: Radiation can be reduced while maintaining high quality in CT colonography
2013-03-12
PROVIDENCE, R.I. – A new study by a Rhode Island Hospital researcher has found it's possible to maintain high-quality CT colonography diagnostic images while reducing the radiation dose. This is important as the use of CT colonography, or virtual colonoscopy, becomes more widely used for colorectal cancer screenings.
Through his research, Kevin J. Chang, M.D., of the department of diagnostic imaging, found that decreasing the tube voltage would not negatively impact the integrity of the CT colongraphy. His research is published in the current issue of the journal Radiology.
"Radiation ...
UF study shows spiders, not birds, may drive evolution of some butterflies
2013-03-12
GAINESVILLE, Fla. --- Butterflies are among the most vibrant insects, with colorations sometimes designed to deflect predators. New University of Florida research shows some of these defenses may be driven by enemies one-tenth their size.
Since the time of Darwin 150 years ago, researchers have believed large predators like birds mainly influenced the evolution of coloration in butterflies. In the first behavioral study to directly test the defense mechanism of hairstreak butterflies, UF lepidopterist Andrei Sourakov found that the appearance of a false head – a wing ...