Grant: Project Grant

The preservation of genetic material is essential for survival. However, cells are continuously exposed to a plethora of DNA-damaging agents (e.g. sunlight, chemicals). If not repaired, damaged DNA can lead to deleterious consequences, ranging from mutations and chromosomal aberrations to cell death. Cells contain sophisticated DNA repair pathways to preserve genome integrity. Our understanding of the mechanisms that underpin these networks is incomplete. This knowledge is of utmost importance since defects in DNA repair lead to various diseases, including neurological defects, immunodeficiency, and cancer. In order to determine how and why errors in DNA repair lead to these pathologies, we first need to understand the fundamental mechanisms of DNA repair and genome stability. Most DNA repair pathways require nucleases, which are molecular scissors that cut damaged and abnormal DNA structures. This is a critical activity because the failure to remove such structures compromises genome stability. In humans, a protein called SLX4 orchestrates the assembly of a large multi-nuclease complex called SMX. I have recently shown that SMX removes DNA structures that would compromise normal cell function. My work highlights an essential role for SMX in DNA repair and genome stability. However, key questions about SMX structure, assembly, and nuclease activity remain to be addressed. The overarching goal of our research is to understand how the SMX complex operates in human cells. Complementary biochemical and cellular approaches will be used to elucidate the molecular interactions that promote SMX assembly and nuclease activity. These studies will provide a solid framework for understanding how the SMX tri-nuclease functions in DNA repair and genome stability. Likewise, this research will significantly advance our understanding of the essential cellular pathways that go awry in a spectrum of human diseases, including cancer.