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.
We have recently defined novels roles for chromatin remodelers. We found that SWI/SNF, known to be important for remodeling chromatin, is also important for activating the DNA damage response. Genes Dev. 2015 Mar 15;29(6):591-602. We have also shown that the INO80 chromatin remodeling complex helps regulate a Rad53 mediated DNA damage checkpoint. Mol Cell. 2015 Jun 4;58(5):863-9. These studies may lead to novel strategies to target DNA damage response and checkpoint proteins as well as chromatin remodeling pathways in 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. We have found that that a mutant form of actin impairs the ability of INO80 to function correctly, implicating nuclear actin in the process of chromatin remodeling – a mechanism that helps regulate the expression of genes. Further we showed that unlike cytoplasmic actin which forms filaments, nuclear actin is monomeric, in fact, actin within the INO80 complex is arranged in such a way that it cannot form filaments. Nat Struc Mol Biol 2013 Apr;20(4):426-32. Understanding the function and mechanism of nuclear actin and its regulators has fundamental implications in our understanding of chromatin and the cell nucleus. Given that actin is a major player in cancer and vascular diseases, our discoveries about nuclear actin provide an exciting new angle for understanding and treating these diseases.