David T. Auble, PhD
Chromatin remodeling and DNA repair in cancer
Research in the Auble lab focuses on understanding the functions of yeast proteins that are essential for DNA repair and transcriptional regulation. An understanding of how regulators of these processes function in human cells has been greatly aided by exploiting the technical advantages of yeast. As the transcription and DNA repair machineries are evolutionarily highly conserved, yeast have provided an excellent system for understanding the functions of these conserved proteins. The central relevance of transcriptional regulation to cancer is substantiated by the discovery of many cellular transcription factors (e.g. myc, myb, jun, fos, Rb and p53) whose mutation leads to cancer. Several of these oncogenic transcription factors are now thought to function by interaction with a basal transcription factor called TATA-binding protein (TBP). The goal of on-going studies is to define how the interaction of TBP and DNA is regulated by the action of Mot1, an essential protein. Remarkably, Mot1 regulates the transcriptional activity of TBP by using ATP hydrolysis to remove TBP from DNA. Mot1 is a member of the Snf2/Swi2 ATPase family; mutations in several family members cause diseases in humans including cancer. The analysis of Mot1 mechanism therefore provides a framework for understanding the molecular basis of human Snf2/Swi2-related proteins and their contributions to disease.
A second goal is to define mechanisms of action and regulation of another Snf2/Swi2 ATPase, Rad16, a yeast protein that plays critical roles in DNA repair. Rad16 is a component of a complex (called NEF4) that links Snf2/Swi2 ATPase activity to a novel ubiquitin-mediated repair pathway. The complex functions by coordinating the activities of the ATPase and the proteasome to alter protein-DNA complexes formed at sites of DNA damage in vivo. Rad16 regulates the levels of the primary UV DNA damage sensor called Rad4. A similar mechanism has recently been shown to pertain in human cells, establishing the relevance of these analyses for understanding mechanisms of genome maintenance in humans. The failure of cells to repair DNA damage by this pathway leads to genomic instability and is a well-established cause of cellular growth deregulation and cancer. An understanding of DNA repair processes is therefore essential to understand how cancer cells develop and to devise new molecular approaches to treat cancer.