Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism controlling DNA damage response has potential novel medical applications

10.10.2005


Production of p53 in response to DNA damage depends on proteins that bind to a control region of the messenger RNA that codes for this protein, according to St. Jude researchers



Investigators at St. Jude Children’s Research Hospital have discovered a previously unrecognized mechanism that controls a key protein linked to the cell’s response to stress - a finding that holds promise for new ways to enhance cancer therapies or protect cells from dying after exposure to damaging chemicals or radiation.

The gene for this protein, called p53, is the most commonly mutated gene in human cancer; and it plays a critical role in helping cells respond to stress, especially stresses that damage DNA, according to researchers.


Previously, the rise in the level of p53 in cells whose DNA had been damaged was thought to be due only to a decrease in the rate at which the p53 protein is broken down in the cell. The St. Jude study showed that the level of p53 protein synthesis increases following DNA damage. This discovery suggests that scientists can use this newly recognized mechanism to modulate p53 function in the cell in order to control whether cells in the body mutate, and whether cells live or die after DNA damage. A report on this work appears in the October 7 issue of the journal Cell.

If a cell has been damaged, p53 protects the body by either preventing that cell from dividing or triggering a cascade of molecular signals that causes that cell to commit suicide¡ªa process called apoptosis. In this way, p53 rids the body of useless cells and prevents cells with potentially cancer-causing mutations from multiplying and spreading. Failure of a cell to activate p53 function after DNA damage can contribute to the generation of genetically altered cells that leads to cancer.

The St. Jude team showed that the competing proteins, ribosomal protein L26 (RPL26) and nucleolin, vie for control of the messenger RNA (mRNA) that codes for p53. mRNA is the decoded form of a gene that acts like a blueprint that the cell’s protein-making machinery (ribosomes) use to make a specific protein. Researchers identified a region of the mRNA, called the 5¡ä-untranslated region (UTR) that serves as a control switch for this process. In undamaged cells, nucleolin binds to this region of p53 mRNA and suppresses synthesis. But after DNA damage, RPL26 binds to this region and increases the translation of the mRNA into the p53 protein.

If the researchers inhibited production of RPL26 in human cells that had been exposed to DNA damaging agents, like ionizing irradiation, the cells with damaged DNA failed to increase p53 protein, and thus failed to stop growing or failed to die as they should have. This demonstrated that RPL26 production is a critical player in the cell’s response to DNA damage. In contrast, when the researchers reduced the levels of nucleolin in cells, p53 production after DNA damage increased.

"Our findings suggest that RPL26 and nucleolin play critical roles in controlling the production of p53 and the response of the cell to ionizing radiation and other types of cellular stress," said Michael Kastan, M.D., Ph.D., director of the St. Jude Cancer Center and chair of hematology-oncology. "Now we would like to use these new insights to develop ways to modulate RPL26 or nucleolin in order to alter p53 function in cells of the body. The ability to increase p53 function in tumor cells could increase the effectiveness of radiation and chemotherapy in treating certain types of tumors."

"On the other hand, these insights provide a potentially novel way to try to decrease levels of p53 so that we could protect cells in normal tissues from dying after exposure to toxins or oxidative damage," he added. Kastan is senior author of the Cell paper.

The discovery of the roles of RPL26 and nucleolin in p53 production may have much broader implications than just the regulation of p53 levels in response to DNA damage, according to Kastan. Hypoxia (low levels of oxygen) and high doses of certain DNA-damaging agents inflict serious stress on cells, causing a general suppression of protein production, Kastan noted. In order to cope with such stress, cells must maintain adequate levels of certain proteins. Therefore, the cell must be able to activate specific mechanisms in response to stress, even when protein production as a whole is being suppressed. The binding of RPL26 to the 5¡äUTR appears to be an example of such a mechanism that bypasses the cell’s usual shut-down of protein synthesis during times of stress, Kastan said.

Carrie Strehlau | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>