The long-term goal the research program generates paradigms for how the protein ubiquitylation regulates chromatin dynamics during DNA replication. Recent evidence has shown that components of the protein ubiquitylation system are involved- directly and mechanistically - in numerous important biological processes- such as gene activation (including co-activator recruitment, co-transcriptional mRNA processing, and transcriptional termination), DNA damage repair and DNA replication. Yet the underlying molecular mechanisms at work remain obscure. To understand the fundamental ways in which ubiquitin (Ub), and Ub-ligases can influence chromatin mediated biological processes, this project focuses on exposing how chromatin structures are modulated by histone ubiquitylation events, how DNA polymerase is modulated by Ub-mediated nucleosome dynamics. These studies take advantage of the chemically synthesized histone carrying site-specific Ub, and employ cutting-edge biochemical and genomic approaches to define both the mechanism and significance of control of transcription and replication by protein ubiquitylation. Results of thes studies will have broad impact in two main areas. First, they will illuminate a poorly understood aspect of DNA replication. It has only recently been appreciated that ubiquitylation is directly involved in replication, and although this is a rapidly evolving field, general themes and processes have yet to be defined. These studies will define these general themes, and in so doing reveal novel ways in which DNA replication is regulated. Results of this work are also likely to impact our understanding of diseases such as cancer. Second, this research will reveal how specific ubiquitylation events may affect chromatin architecture, which underlie many distinct biological processes. An emerging theme in this project is that ubiquitylation may alter inter- nucleosome interactions and thus regulate accessibility of specific part of the genome. As the ubiquitylation plays a prominent role in cellular homeostasis and is dysregulated in a wide spectrum of human diseases, results of these studies will also have broad impact beyond the immediate field of chromatin biology.
Analyses of functional relationship of histone ubiquitylation and chromatin dynamics during DNA replication is of significant importance because: (a) accumulated or inherited abnormality in histone modifications impair normal gene expression and cause progression of human diseases including cancer, metabolic disorders, autoimmune disease, juvenile and type 1/2 diabetes and diabetic complications, cardiac hypertrophy and asthma, all of which display aberrant gene expression, (b) deregulation of histone modifying enzymes is the primary cause of human malignancies including cancer, (c) cumulative changes in histone modifications correlate with progression of aging-related diseases.
