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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084983-06
Application #
8304965
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Janes, Daniel E
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$297,950
Indirect Cost
$111,731
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104