Chromatin remodeling is crucial in the regulation of transcription, DNA replication, recombination and repair. Disruptions of these processes can lead to misregulation of genes and failure in DNA damage repair, which are two major underlying causes of human cancer. The long-term goal of my research is to understand how chromatin is remodeled to allow diverse nuclear processes to occur in an orderly fashion and how these processes may be altered in cancer cells. Recently, actin related proteins (Arps) as well as conventional actin have been found as subunits of a number of evolutionarily conserved chromatin remodeling enzyme complexes from yeast to human, including histone acetyltransferase complexes (HATs) and ATP-dependent chromatin remodeling complexes. However, little is known about the function of these proteins in the cell nucleus. We propose that nuclear actin and Arps directly participate in chromatin remodeling and affect gene expression as well as DNA repair, two processes that are frequently disrupted in cancer cells. Combining biochemical and genetic approaches, we use baker's yeast, Saccharomyces cerevisiae, to address the following: 1) The role of Arps in ATP-dependent chromatin remodeling. 2) Interactions between Arps and chromatin. 3) Function of nuclear actin in chromatin remodeling. These studies will fill gaps in our knowledge of actin and Arps, lead to a better understanding of chromatin remodeling mechanism during gene regulation and DNA repair, and provide new insights into the causes of cancer. Ultimately, my research may provide novel targets for cancer detection and treatment.
