Roles for the human sirtuin SIRT7 in chromatin regulation and cancer
Abstract/Contents
- Abstract
- Sirtuins are a conserved family of NAD+-dependent deacetylases that regulate diverse biological processes including genomic stability, metabolism, and aging. SIRT7 is a mammalian sirtuin whose enzymatic activity and physiologic functions have been unclear. Here I present work aimed at elucidating the biochemical, molecular, and cellular roles of human SIRT7. In Chapter 1, I report the discovery that SIRT7 possesses deacetylase activity specific for histone H3 acetylated at lysine 18 (H3K18Ac). In genome-wide binding studies, we find that SIRT7 associates with promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. In Chapter 2, I discuss the identification of a novel SIRT7 interacting protein, the ETS transcription factor ELK4. Our work suggests that ELK4 plays an important role in defining the spectrum of SIRT7 target genes, by recruiting SIRT7 to a subset of promoters. In Chapter 3, I present our work establishing new functions for SIRT7 in cancer progression. Notably, selective hypoacetylation of H3K18Ac has recently been linked to oncogenic transformation, and in patients is associated with aggressive tumor phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells including anchorage independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by viral oncoproteins. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, this work establishes SIRT7 as the first known site-specific H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs, and tumor formation in vivo.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Barber, Matthew Frederick |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Gozani, Or Pinchas |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Frydman, Judith |
| Advisor | Chua, Katrin Faye |
| Advisor | Frydman, Judith |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Matthew Frederick Barber. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Ph. D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Matthew Frederick Barber
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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