Grant: Foundation Grant

Most mutations in human DNA that cause disease are not in sequences that code for protein but rather in regulatory sequences that determine whether particular proteins, or parts of proteins, are made. These regulatory sequences are recognized by about 1600 regulatory proteins called transcription factors. We are studying a large family of more than 700 transcription factors known as the zinc finger proteins. We have unexpectedly discovered that the zinc finger proteins almost always recognize RNA as well as DNA and propose to identify the sequences that they recognize. This will enable better understanding of human disease and help us to better predict both what diseases might occur and how best to treat those diseases. We are also studying several proteins in which mutations cause three devastating and fatal neurodegenerative diseases, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS; also as known as Lou Gehrig's disease) and fronto-temporal dementia, as well as another protein important for the growth of many kinds of cancer cells. We propose to determine how the zinc finger proteins control the splicing together of RNA fragments to form contiguous segments that code for protein, as well as how the zinc finger proteins, the neurodegeneration proteins, and the cancer-promoting protein determine where RNA polymerase II, the enzyme that reads human genes, stops at the ends of genes. We will also try to identify chemicals that prevent RNA polymerase II from stopping and might be developed into new kinds of anti-cancer drugs.