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JRE Dissertation 2015.pdf (4.96 MB)

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Histone H4 Acetylation in the DNA Damage Response and Telomere Formation of Schizosaccharomyces pombe

Eisenstatt, Jessica R
http://rave.ohiolink.edu/etdc/view?acc_num=case1440417554

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Cells are regularly subjected to exogenous and endogenous processes that damage DNA which may result in double strand breaks (DSBs). Specialized sensor proteins recognize these breaks and trigger a cellular response leading to cell cycle arrest and/or apoptosis. Telomeres, the ends of linear eukaryotic chromosomes, are structurally similar to DSBs, but are not recognized as such and are associated with proteins that protect the ends from degradation. This blocks the activation of cell cycle arrests and allows normal cellular growth. Both DSBs and telomeres exist in the context of chromatin, and post-translational modifications (PTMs) on histone proteins regulate the recognition of both cellular processes. In fission yeast and mammalian cells, checkpoint proteins are recruited to sites of damage through recognition of and interaction with dimethylated histone H4 lysine 20 (H4K20me2) and phosphorylated H2A in fission yeast or H2AX in mammals (gamma-H2AX). At the telomere, dimethylated histone H3 lysine 9 (H3K9me2) is the major mark of heterochromatin. While some PTMs have been well-studied in multiple model organisms, many require further investigation. An inadequately studied histone modification in Schizosaccharomyces pombe, acetylated histone H4 lysine 16 (H4K16ac), has been implicated to act in the mammalian DNA damage response (DDR) and heterochromatin maintenance at the telomere and mating type locus of the evolutionarily distant budding yeast, Saccharomyces cerevisiae. In both cases, it appears that the ability to switch between the acetylated and unacetylated states is necessary for proper maintenance. To study the direct role of the dynamics of H4K16 in the DDR and at the telomere in S. pombe, strains that mimic the constitutively acetylated and unacetylated states of H4K16 were constructed. Surprisingly, blocking the ability to regulate the acetyl state of H4K16 had only small effects on the response to DNA damaging agents, which were enhanced when combined with histone H3 acetyltransferase deletions. These results suggest that dynamics of H4K16ac moderately regulate the S. pombe DDR and likely work in parallel to a residue on histone H3. Additionally, mutating H4K16 had no effect on telomeric gene silencing, suggesting that H3K9me2 plays the predominant role in fission yeast silencing directly adjacent to the telomere. This work provides insight into the regulation of chromatin stability and structure through chromatin-associated modifications.
Kurt Runge, PhD (Advisor)
Hung-Ying Kao, PhD (Committee Chair)
David Samols, PhD (Committee Member)
Peter Harte, PhD (Committee Member)
Peter Scacheri, PhD (Committee Member)
170 p.
Biochemistry; Genetics; Molecular Biology
Schizosaccharomyces pombe; histone proteins; histone H4; H4K16; H4K16ac; histone acetylation; DNA damage; telomere; fission yeast;

Recommended Citations

Citations

  • Eisenstatt, J. R. (2016). Histone H4 Acetylation in the DNA Damage Response and Telomere Formation of Schizosaccharomyces pombe [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1440417554

    APA Style (7th edition)

  • Eisenstatt, Jessica. Histone H4 Acetylation in the DNA Damage Response and Telomere Formation of Schizosaccharomyces pombe. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1440417554.

    MLA Style (8th edition)

  • Eisenstatt, Jessica. "Histone H4 Acetylation in the DNA Damage Response and Telomere Formation of Schizosaccharomyces pombe." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1440417554

    Chicago Manual of Style (17th edition)

case1440417554
666
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.