The discovery by a Cornell University and Weill Cornell Medical College scientist that poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in gene transcription could open doors to new therapies for cancer and neurological disease, and even hints at connections between the foods we eat and gene expression within our cells.
"What's catching people's attention is that we've actually characterized a whole new activity for this long-studied protein," said Dr. W. Lee Kraus, Associate Professor of Molecular Biology and Genetics at Cornell University in Ithaca, and Adjunct Associate Professor of Pharmacology at Weill Cornell Medical College in New York City.
"It's a very, very exciting story," added Dr. Anthony Sauve, an Assistant Professor of Pharmacology at Weill Cornell Medical College. Dr. Sauve is currently developing drugs that either activate or inhibit PARP-1.
"Dr. Kraus's work is really important," he said, "because he found that PARP-1 is regulating gene transcription -- converting DNA from an active to a silent state. So the real question is, what genes are affected? And for those genes that are either up-regulated in disease or down-regulated, is there a way we can target PARP-1 to turn the genes on or off?"
The findings from Dr. Kraus's lab were published in the December 17, 2004 issue of Cell.
PARP-1 is the most abundantly expressed member of a family of proteins long known to be involved in the metabolism of nicotinamide adenine dinucleotide (NAD+), a cellular co-factor involved in both energy use and signaling within cells. According to Dr. Kraus, the enzyme has also been implicated in processes surrounding cellular stress and DNA damage.
But in their experiments in both human and fly cells, Dr. Kraus's team in Ithaca discovered that PARP-1 also influences gene transcription within the cell nucleus.
"We found that, on its own, PARP-1 binds very specifically to the chromatin structures that surround genes, called nucleosomes. When PARP-1 binds to chromatin, it actually tightens those structures -- closing up that architecture and making it much more difficult for genes to become expressed," he said.
But another natural mechanism can also release genes from PARP-1's repressive grip, the Cornell team found. When the enzyme binds with NAD+, this chemical partnership causes PARP-1 to convert the NAD+ into long chain polymers on its surface. Those polymers cause it to lose its connection to a gene's chromatin shell.
"PARP-1 then dissociates from chromatin, the structure opens up -- and genes are free to be expressed again," Dr. Kraus explained. The implications of these discoveries could be profound, he said. By manipulating the NAD+/PARP-1 mechanism, scientists may find new pharmacological ways of switching genes on and off at will.
"Right now, no one is certain exactly which genes are going to be regulated by this system," Dr. Sauve said. "That's where the pharmacological approaches are going to be useful." Currently, Dr. Sauve's lab at Weill Cornell is hard at work identifying candidate genes, as well as drugs that might intervene in the PARP-1 system. Of course, it may take years before this type of gene therapy reaches patients. But studies are suggesting PARP-1 may play a role in a wide variety of conditions.
Because cancer is essentially driven by genetic abnormalities, it's an obvious research goal, according to the experts. But Dr. Sauve also pointed to recent animal studies that found that inhibition of PARP-1 activity is associated with neurological and learning impairment. PARP-1 activity has also been implicated in immune responses, diabetes, and aging.
Finally, there's the intriguing possibility that the NAD+/PARP-1 system might connect daily diet to genetic activity within cells. "For example, NAD+ is actually synthesized in a special biological pathway that uses niacin -- vitamin B3. It's not been proven yet, but it suggests that dietary effects could have a greater impact on gene expression than we even knew before," Dr. Kraus said. "That's another surprise PARP-1 may one day have in store."
Dr. Kraus's work is funded by grants from both the National Institutes of Health and the American Cancer Society. Co-authors on the Cell study include lead author Dr. Mi Young Kim, Dr. Nicolas Gevry, Dr. John T. Lis, and Dr. Steven Mauro -- all of Cornell University, Ithaca, NY.