As many as 20,000 lesions occur daily in a cells 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. Thats 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
|Contact: Anne Rueter|
University of Michigan Health System