MERIT Award Recipient: Arnold J. Berk, M.D.
Biosynthesis of Adenovirus Early RNAs
Dr. Berk's MERIT award research concerns the molecular mechanisms that control the transcription of genes into messenger RNAs. This fundamental process determines which of the ~35,000 human genes is expressed in each of the several trillion cells that make up the human body. As a result, control of transcription determines the properties of each of these cells, including normal cells involved in beneficial physiological processes and abnormal cells involved in disease. The molecular mechanisms that control transcription are complex, as might be expected for a process that is the basis of the development, growth and function of something as complex as the human body.
About two thousand regulatory transcription factors can be combined in different ways to control the transcription of each human gene. These regulatory transcription factors interact with multiprotein complexes that control the way each gene is packaged into a complex with proteins called chromatin. Following the proper organization of chromatin structure, regulatory transcription factors next bind to a recently discovered multiprotein complex called "mediator." This in turn binds to the RNA polymerase enzyme, which reads the base sequence of the gene and copies it into a messenger RNA precursor that is then processed in subsequent steps into protein. Currently, it is thought that several regulatory transcription factors interact with the mediator complex simultaneously so that their respective signals can be integrated to determine the frequency of transcription of each gene, and hence the amount of protein encoded by each gene that is expressed in each cell, which determines the cells characteristics and functions.
Dr. Berk has concentrated his research on the transcription of genes of a virus, adenovirus, as a model system for understanding principles of transcription control that can be applied to cellular genes as well as viral genes. These studies have led him to focus much of his laboratory's work on one subunit of the mediator complex, called Sur2. His recent research results revealed that the Sur2 mediator subunit is important in the responses cells make to signals from neighboring cells that control cell replication and differentiation. Current and future research will analyze how interactions between Sur2 and viral and cellular regulatory transcription factors control transcription.
Principles uncovered in studies of the function of Sur2 are likely also to apply to other components of the mediator complex. A full understanding of the molecular interactions that control transcription may lead to new strategies for therapeutic interventions that would allow physicians to manipulate gene expression in specific cells. This potentially would be applicable to the treatment of multiple diseases including autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, as well as the suppression of tumor cell replication for the treatment of cancer.