The study looked at two RNA polymerases known as polymerase I and II (Pol I and Pol II) in brewer’s yeast cells, which is an established model for higher organisms. RNA polymerases are enzymes that make RNA based on the genetic code found in DNA. Pol I and Pol II have separate but similar cellular roles. In essence, Pol I makes the RNA that forms the bulk of ribosomes - the factories that make protein - and Pol II makes RNA that the ribosomes use as templates, or recipes, for making proteins.“Science has long assumed that any changes or mutations in similar regions of one RNA polymerase will have the same effect on related RNA polymerases,” said David Schneider, Ph.D., assistant professor in the Department of Biochemistry and Molecular Genetics and primary investigator of the study. “We found, to our surprise, that mutations in Pol I that are identical to known mutations in Pol II did not have the same effects on polymerase activity. This finding identifies unique features of Pol I that could potentially be exploited to develop drugs that target one polymerase while not interfering in function of the other.”
Schneider says where this may have applications for human health lies in controlling the rapid and unregulated cell growth associated with cancer. Controlling the production of ribosomes is an excellent way to control cell growth. He points to the need to discover what are called rate-limiting steps during the process of making RNA.
“We can think of polymerases as small machines that build chains. In each step of transcription, a new link is added to the end of the growing RNA chain” he said. “There are a number of chemical steps involved in adding another link to the chain. If one of those steps is slower than the others, that step limits the overall chain growth rate. Our results suggest that Pol I and Pol II might have different rate-limiting steps, and those steps, particularly in Pol I, may be good targets for intervention to control the growth of cancer cells.”
Schneider says researchers have begun to take a closer look at RNA polymerase I as a potential target for cancer chemotherapy, but he stresses that his work is fundamental science, geared at developing a better understanding of the basic biology of the cell.
“The long-term goal would be to find therapeutic agents that inhibit the rate-limiting step in transcription by RNA polymerase I, resulting in slower cell growth,” Schneider said. “It’s a promising and fascinating field of study.”
The research was performed in collaboration with labs at the University of Virginia and Texas A&M University and was funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.