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 Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>