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Enzyme alerts cell's powerful army to repair DNA damage
September 06, 2007New view of how damage is detected aids understanding of cancer, aging and neurological diseases
ANN ARBOR, Mich. - Scientists know that inside each cell, a little engine called RNA polymerase II does one essential job: It copies instructions from genes in the nucleus that get carried to production units in the rest of the cell to support our daily needs. Now researchers at the University of Michigan Medical School have shown that RNA polymerase II also constantly scans the cell's DNA for damage. When certain types of damage in DNA halt the action of RNA polymerase II, a stress signal is generated that alerts a key tumor-suppressor protein called p53.
The activities of p53, a master protein that responds to DNA damage by marshaling hundreds of genes to repair or eliminate damaged cells, have been the subject of thousands of studies. Mutations in the p53 gene occur in more than half of all cancers.
"We have come up with a new paradigm for how cells protect themselves against cancer-producing DNA lesions," says Mats Ljungman, Ph.D., a U-M researcher and lead author of a recent study in the Proceedings of the National Academy of Sciences.
"Much is known already about p53, but this adds a significant piece of knowledge about how it is activated," Ljungman adds. He is an associate professor in the Department of Radiation Oncology in the Division of Radiation and Cancer Biology at the U-M Comprehensive Cancer Center and associate professor of Environmental Health Sciences at the U-M School of Public Health.
A commentary in the journal praised the U-M study and urged more attention to RNA polymerases as major sensors "for all DNA damage response reactions."
Ljungman says the findings have implications for the study of cancer, aging and neurological diseases. Figuring out precisely how cells detect and repair damage is crucial in understanding what goes wrong in cancer, in which harmful mutations can elude the body's ability to control cell division.
Finding and repairing DNA lesions is a non-stop job for cells.
As many as 20,000 lesions occur daily in a cell's DNA, Ljungman says. Many stresses result from oxidation and other internal cell processes. In addition, our DNA is also challenged by sunlight, radiation and reactive chemicals found in food.
"So much damage happens all the time," Ljungman says. "That puts pressure on cells to efficiently scan the DNA and do something about it. That's what we think the transcription machinery is doing."
RNA polymerase II is the main enzyme involved in transcription, the process of reading the genetic code. The U-M team did a series of experiments to find out what happens when transcription is blocked. They found that using transcription-blocking agents such as ultraviolet light resulted in activation of the p53 stress response, independent of other cell processes.
When they micro-injected an anti-RNA polymerase agent into human cell nuclei, they found that p53 proteins then accumulated in the cell nucleus - one aspect of the stress response - even when no DNA damage occurred. Ljungman and his colleagues also discovered what happens when RNA polymerase II gets stuck on a kink or other lesion in the DNA. It sends a signal via two proteins that activate p53.
"These two proteins are saying, 'Transcription has stopped,'" says Ljungman. These early triggers act like the citizen who smells smoke and sounds a fire alarm, alerting the fire department. Then p53, like a team of fire fighters, arrives and evaluates what to do. To reduce the chance of harmful mutations that may result from DNA damage, p53 may kill cells or stop them temporarily from dividing, so that there is time for DNA repair.
Learning more about the processes involved in transcription could pay off in improved treatments in years to come. Cisplatin, a drug used to treat testicular and ovarian cancer, acts by stopping transcription and causing cells to die. Some other chemotherapy drugs block transcription too. But these types of drugs also damage a cancer patient's DNA in normal tissues, sometimes leading to other cancers later.
The study's findings eventually could lead to better drugs that might target transcription directly without those ill effects, Ljungman believes.
University of Michigan Health System
"We have come up with a new paradigm for how cells protect themselves against cancer-producing DNA lesions," says Mats Ljungman, Ph.D., a U-M researcher and lead author of a recent study in the Proceedings of the National Academy of Sciences.
"Much is known already about p53, but this adds a significant piece of knowledge about how it is activated," Ljungman adds. He is an associate professor in the Department of Radiation Oncology in the Division of Radiation and Cancer Biology at the U-M Comprehensive Cancer Center and associate professor of Environmental Health Sciences at the U-M School of Public Health.
A commentary in the journal praised the U-M study and urged more attention to RNA polymerases as major sensors "for all DNA damage response reactions."
Ljungman says the findings have implications for the study of cancer, aging and neurological diseases. Figuring out precisely how cells detect and repair damage is crucial in understanding what goes wrong in cancer, in which harmful mutations can elude the body's ability to control cell division.
Finding and repairing DNA lesions is a non-stop job for cells.
As many as 20,000 lesions occur daily in a cell's DNA, Ljungman says. Many stresses result from oxidation and other internal cell processes. In addition, our DNA is also challenged by sunlight, radiation and reactive chemicals found in food.
"So much damage happens all the time," Ljungman says. "That puts pressure on cells to efficiently scan the DNA and do something about it. That's what we think the transcription machinery is doing."
RNA polymerase II is the main enzyme involved in transcription, the process of reading the genetic code. The U-M team did a series of experiments to find out what happens when transcription is blocked. They found that using transcription-blocking agents such as ultraviolet light resulted in activation of the p53 stress response, independent of other cell processes.
When they micro-injected an anti-RNA polymerase agent into human cell nuclei, they found that p53 proteins then accumulated in the cell nucleus - one aspect of the stress response - even when no DNA damage occurred. Ljungman and his colleagues also discovered what happens when RNA polymerase II gets stuck on a kink or other lesion in the DNA. It sends a signal via two proteins that activate p53.
"These two proteins are saying, 'Transcription has stopped,'" says Ljungman. These early triggers act like the citizen who smells smoke and sounds a fire alarm, alerting the fire department. Then p53, like a team of fire fighters, arrives and evaluates what to do. To reduce the chance of harmful mutations that may result from DNA damage, p53 may kill cells or stop them temporarily from dividing, so that there is time for DNA repair.
Learning more about the processes involved in transcription could pay off in improved treatments in years to come. Cisplatin, a drug used to treat testicular and ovarian cancer, acts by stopping transcription and causing cells to die. Some other chemotherapy drugs block transcription too. But these types of drugs also damage a cancer patient's DNA in normal tissues, sometimes leading to other cancers later.
The study's findings eventually could lead to better drugs that might target transcription directly without those ill effects, Ljungman believes.
University of Michigan Health System
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