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 Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie

nachricht Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>