DNA Damage Response and Cancer Epigenetics
DNA damage is detrimental to the cell, and can lead to diseases such as cancer. In eukaryotic cells, the damaged DNA exists in the context of chromatin, the natural substrate for the DNA repair machinery. Eukaryotic cells utilize chromatin-modifying complexes to regulate chromatin by ATP-dependent perturbations of histone-DNA interactions, or by covalent post-translational modification (PTM) of the histones. The long-term goal of our research in this area is to understand how chromatin is modified to allow DNA repair to occur in an orderly fashion after DNA is damaged, and how changes in chromatin modification lead to human diseases such as cancer.
We have performed pioneering studies linking ATP-dependent chromatin remodeling to DNA repair, checkpoint regulation and DNA replication. These studies provide a new paradigm for how a chromatin-remodeling complex can respond to DNA damage. We have also begun to ask broader questions of how other chromatin factors, such as histones and histone modifications, are involved in DNA damage response and cancer epigenetics. These studies will reveal novel mechanisms for maintaining genome integrity, and uncover new chromatin targets for cancer treatment.
Nuclear Actin and its Regulators
Recent advances in chromatin research have identified conventional actin, as well as actin-related proteins (Arps), as subunits of many chromatin-modifying complexes. Like histones, actin is one of the most important and conserved molecules of the cell. While the roles of actin in the cytoplasm are well established, the presence and function of actin in the nucleus remain poorly defined. The mystery of nuclear actin has remained a challenge to biologists for several decades, due to the lack of a defined system in which the function of nuclear actin can be cleanly dissected biochemically and genetically.
Taking advantage of the evolutionarily conserved actin- and Arp-containing INO80 chromatin remodeling complex and the yeast genetic system with a single actin gene, we have developed a system to address the mechanisms of nuclear actin and its regulators. Our findings suggest that nuclear actin has fundamental and ancient functions in chromatin regulation. However, the mechanisms of nuclear actin in chromatin regulation are highly distinct from actin mechanisms in the cytoplasm. Understanding the function and mechanism of nuclear actin and its regulators has fundamental implications in our understanding of chromatin and the cell nucleus. In addition, the novel mechanisms of nuclear actin provide a new window for cancer treatment, since actin is an important driver for cell differentiation and metastasis.