To the telomeres and beyond : chromatin regulation by the mammalian sirtuin SIRT6
Abstract/Contents
- Abstract
- Saccharomyces cerevisiae silent information regulator 2 (Sir2) is an NAD+-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism, and lifespan regulation. The human Sir2 family member SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including preserving telomere integrity, fine-tuning gene expression programs, preventing genomic instability, and maintaining metabolic homeostasis. Here, we describe work aimed at expanding the molecular and cellular understanding of SIRT6. First, we report the identification of novel functions for the N- and C-terminal domains of SIRT6. We show that the C-terminal extension (CTE) of SIRT6 contributes to proper nuclear localization; the N-terminal extension (NTE) is critical for chromatin association and intrinsic catalytic activity; and mutation of a conserved catalytic histidine residue in the core sirtuin domain not only abrogates SIRT6 enzymatic activity but also leads to impaired chromatin association in cells. Second, we show that SIRT6 is required for maintenance of telomere-proximal gene silencing--a phenomenon termed telomere position effect (TPE)--in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these studies provide new insight into the molecular mechanism of SIRT6 activity; uncover a novel role for SIRT6 in regulating telomeric gene silencing; and reveal important links between SIRT6 and disease-relevant cellular processes.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2012 |
| Publication date | 2011, c2012; 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Tennen, Ruth Ilana |
|---|---|
| Associated with | Stanford University, Program in Cancer Biology. |
| Primary advisor | Chua, Katrin Faye |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Advisor | Brunet, Anne, 1972- |
| Advisor | Gozani, Or Pinchas |
| Advisor | Lipsick, Joseph Steven, 1955- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Ruth Ilana Tennen. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Ph. D. Stanford University 2012 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Ruth Ilana Tennen
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...