Role of histone methylation and variants in genome function Public Deposited

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  • March 19, 2019
Creator
  • Jha, Deepak
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • The eukaryotic genome is compacted in the form of chromatin, which is a complex of DNA and histone proteins. Regulation of chromatin structure influences all aspects of cellular processes, especially the DNA -dependent processes. The basic unit of chromatin is composed of DNA wrapped around a core of octameric histones, forming what is called the nucleosome core particle. The dynamic nature of this structure implies that there will be well-regulated processes and pathways that help in the interchanges between one form of chromatin and another. In chapter 1, I outline the current state of literature for mechanisms that regulate chromatin structure, with special emphasis on histone modifications and histone variants. I also review the literature for genome maintenance and how chromatin regulates genomic integrity. One of the most critical histone modifications that regulate chromatin structure is the methylation of histone H3 at lysine 36 (H3K36me). Set2 catalyzes H3K36me and its function is well established in regulation of chromatin structure during transcription elongation, but its function in maintaining the integrity of yeast genome was not known. In chapter 2, I describe its novel function in regulating chromatin structure after double strand break (DSB). Work from chapter 2 reveals that Set2-dependent H3K36me (2/3) and its interaction with RNA polymerase II (RNAPII) is critical for surviving DSBs after phleomycin. It also shows that H3K36me is critical for full activation of a DSB checkpoint. Furthermore, I show that H3K36me is also important for chromatin remodeling around a DSB, abrogation of which subsequently facilitates inappropriate end-processing. In chapter 3, I describe our ongoing efforts to delineate the dynamic incorporation/eviction of the histone variant Htz1 in yeast. I show that deletion of NAP1 and CHZ1 results in increased retention of Htz1 in yeast chromatin, and show that there are two non-overlapping surfaces on the Htz1-H2B nucleosome. Furthermore we show that specific point mutations of these residues have biochemical and biological effects on cells. In chapter 4, I describe the implications of my research, place it in the wider context of chromatin research and discuss the contribution of H3K36me and Htz1 in tumorigenesis.
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  • In Copyright
Advisor
  • Strahl, Brian
  • Ramsden, Dale
  • Bloom, Kerry
  • Cook, Jean
  • Bultman, Scott
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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  • This item is restricted from public view for 2 years after publication.
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