Out of chaos, control: Cornell molecular biologists have discovered how a protein called PARP-1 binds to genes and regulates their expression across the human genome. Knowing where PARP-1 is located and how it works may allow scientists to target this protein to battle common diseases, such as stroke and cancer.
Their research is published in the Feb. 8 issue of the journal Science.
"This finding was unexpected -- especially since it entails a broad distribution of PARP-1 across the human genome and a strong correlation of the protein binding with genes being turned on," said co-author W. Lee Kraus, a Cornell associate professor of molecular biology who has a dual appointment at Weill Cornell Medical College in New York City. "Our research won't necessarily find cures for human diseases, but it provides molecular insight into the regulation of gene expression that will give us clues for where to look next."
By knowing where the PARP-1 protein is located in the genome, scientists can better understand the effects of synthetic chemical inhibitors of PARP-1 activity. Such chemicals are being explored for the treatment of stroke, heart disease, cancer and other human diseases. Thus, conceivably, if a patient has a stroke, researchers may one day use PARP-1 inhibitors as part of the therapy, or use PARP-1 to target cancer, said Kraus.
He explained that PARP-1 and another genome-binding protein called histone H1 compete with each other to bind to gene "promoters" (the on-off switches for genes); H1 turns genes "off" while PARP-1 turns them "on." The new study, said Kraus, shows that for a surprising number of genes, only PARP-1 is present, helping to keep those genes turned on.
When human cells are exposed to such physiological signals as hormones or to such stress signals as metabolic shock or DNA damage caused by agents like ultraviolet light, they take action. One of the cellular responses is the production of NAD (nicotinamide adenine dinucleotide), a metabolic communication signal. NAD promotes the removal of PARP-1 from the genome and alters its ability to keep genes on, the scientists have found.
"Think of PARP-1 as a key regulator of gene expression in response to normal signals and harmful stresses," said Kraus. "If you could control most of the traffic lights in a city's street grid with one hand, this is analogous to controlling gene expression across the genome with PARP-1. Under really adverse conditions, you can set all the lights to stop."
The article was also authored by graduate student Raga Krishnakumar and postdoctoral researcher Matthew J. Gamble (both first co-authors) and graduate students Kristine M. Frizzell, Jhoanna G. Berrocal and Miltiadis Kininis, all at Cornell.
The National Institutes of Health funded the research.