The overall goal of this proposal is to understand how ATP-dependent chromatin remodelers influence diverse biological processes. The experiments outlined here focus on understanding how the CSB (Cockayne Syndrome complementation group B) chromatin remodeler modulates chromatin structure and how defects in this protein lead to disease. ATPdependent chromatin remodelers alter chromatin structure non-covalently to regulate DNA access and/or space nucleosomes. Thus, these activities play important roles in regulating nuclear processes such as transcription, replication and DNA repair as well as developmental events including transcriptional memory and cell-fate determination. Mutations in CSB lead to Cockayne syndrome: a disease in which patients are highly sensitive to UV light, age prematurely, and suffer from profound developmental and neurological disorders. CSB plays a pivotal role in transcription-coupled DNA repair; however, little is known as to how its remodeling activity influences this process. The availability of mutant CSB cell lines that phenocopy some of the defects associated with Cockayne syndrome (such as UV sensitivity) makes CSB an excellent candidate remodeler to elucidate the relationship between the biochemical activities and biological functions of ATPdependent chromatin remodeling complexes. To obtain greater insight into the mechanism whereby CSB remodels chromatin, and to elucidate the contribution of this activity to normal development, DNA repair and disease, we propose three aims (1) Dissect the mechanism of CSB remodeling activity, (2) Dissect the functions of CSB in transcription-coupled DNA repair, and (3) Investigate the impact of CSB-binding proteins on CSB function. PUBLIC HEALTH REVELANCE: Chromatin is the fundamental template for all nuclear process and there are countless examples of human disease resulting from misregulation of chromatin structure, including cancer. This proposed research project will not only reveal the underlying mechanism that directly lead to the devastating disease Cockayne syndrome, but offer important insights into the fundamental principles that regulate chromatin structure.
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