Mechanism Controlling DNA Damage Response Has Potential Novel Medical Applications

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

Previously,the rise in the level of p53 in cells whose DNA had been damaged wasthought to be due only to a decrease in the rate at which the p53protein is broken down in the cell. The St. Jude study showed that thelevel of p53 protein synthesis increases following DNA damage. Thisdiscovery suggests that scientists can use this newly recognizedmechanism to modulate p53 function in the cell in order to controlwhether cells in the body mutate, and whether cells live or die afterDNA damage. A report on this work appears in the October 7 issue of thejournal Cell.

If a cell has been damaged, p53 protects the bodyby either preventing that cell from dividing or triggering a cascade ofmolecular signals that causes that cell to commit suicide—a processcalled apoptosis. In this way, p53 rids the body of useless cells andprevents cells with potentially cancer-causing mutations frommultiplying and spreading. Failure of a cell to activate p53 functionafter DNA damage can contribute to the generation of geneticallyaltered cells that leads to cancer.

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

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

“Ourfindings suggest that RPL26 and nucleolin play critical roles incontrolling the production of p53 and the response of the cell toionizing radiation and other types of cellular stress,” said MichaelKastan, M.D., Ph.D., director of the St. Jude Cancer Center and chairof hematology-oncology. “Now we would like to use these new insights todevelop ways to modulate RPL26 or nucleolin in order to alter p53function in cells of the body. The ability to increase p53 function intumor cells could increase the effectiveness of radiation andchemotherapy in treating certain types of tumors.”

“On the otherhand, these insights provide a potentially novel way to try to decreaselevels of p53 so that we could protect cells in normal tissues fromdying after exposure to toxins or oxidative damage,” he added. Kastanis senior author of the Cell paper.

The discovery of the rolesof RPL26 and nucleolin in p53 production may have much broaderimplications than just the regulation of p53 levels in response to DNAdamage, according to Kastan. Hypoxia (low levels of oxygen) and highdoses of certain DNA-damaging agents inflict serious stress on cells,causing a general suppression of protein production, Kastan noted. Inorder to cope with such stress, cells must maintain adequate levels ofcertain proteins. Therefore, the cell must be able to activate specificmechanisms in response to stress, even when protein production as awhole is being suppressed. The binding of RPL26 to the 5′UTR appears tobe an example of such a mechanism that bypasses the cell’s usualshut-down of protein synthesis during times of stress, Kastan said.

The other authors of this study include Masatoshi Takagi, Michael J. Absalon and Kevin G. McLure.
This work was supported in part by the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital
St.Jude Children's Research Hospital is internationally recognized for itspioneering work in finding cures and saving children with cancer andother catastrophic diseases. Founded by late entertainer Danny Thomasand based in Memphis, Tenn., St. Jude freely shares its discoverieswith scientific and medical communities around the world. No familyever pays for treatments not covered by insurance, and families withoutinsurance are never asked to pay. St. Jude is financially supported byALSAC, its fund-raising organization.