Regulation of neuronal genomic integrity through histone deacetylase cooperativity
Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017.
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | eng |
| Published: |
Massachusetts Institute of Technology
2017
|
| Subjects: | |
| Online Access: | http://hdl.handle.net/1721.1/110886 |
| _version_ | 1826204457029861376 |
|---|---|
| author | Dobbin, Matthew Milnes |
| author2 | Li-Huei Tsai. |
| author_facet | Li-Huei Tsai. Dobbin, Matthew Milnes |
| author_sort | Dobbin, Matthew Milnes |
| collection | MIT |
| description | Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. |
| first_indexed | 2024-09-23T12:55:21Z |
| format | Thesis |
| id | mit-1721.1/110886 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T12:55:21Z |
| publishDate | 2017 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1108862019-04-10T14:03:23Z Regulation of neuronal genomic integrity through histone deacetylase cooperativity Dobbin, Matthew Milnes Li-Huei Tsai. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences. Brain and Cognitive Sciences. Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017. Cataloged from PDF version of thesis. Includes bibliographical references (pages 113-119). While the mechanisms preserving genomic integrity are well defined in proliferating cells, corresponding pathways in postmitotic neurons remain poorly understood. In this report, I characterize the functions of two lysine deacetylases, SIRT1 and HDAC1, in the neuronal response to DNA double strand breaks (DSBs). Both SIRT1 and HDAC1 were previously shown to promote neuronal survival in a mouse model of neurodegeneration in which the appearance of DSBs precedes other neurotoxic symptoms. Here I show for the first time the recruitment of both SIRT1 and HDAC1 to sites of DNA DSBs in neurons, where they work cooperatively to coordinate DSB signaling and DNA repair. SIRT1 physically binds HDAC1 and this interaction is strengthened upon DNA damage. I demonstrate that SIRT1 deacetylates HDAC1 at a critical lysine residue, K432, and stimulates its enzymatic activity. Moreover, HDAC1 mutants that mimic a constitutively acetylated state render neurons more susceptible to DNA damaging agents, and pharmacological SIRT1 activators that promote HDAC1 deacetylation also mitigate neuronal loss in a mouse model of neurodegeneration. I propose that the interaction between SIRT1 and HDAC1 constitutes an essential step in the DNA damage response that could be exploited to enhance neuronal survival in various neurodegenerative diseases. by Matthew Milnes Dobbin. Ph. D. in Neuroscience 2017-08-01T13:14:33Z 2017-08-01T13:14:33Z 2015 2017 Thesis http://hdl.handle.net/1721.1/110886 994208152 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 121, 1008-1015, [10] pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Brain and Cognitive Sciences. Dobbin, Matthew Milnes Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title | Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title_full | Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title_fullStr | Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title_full_unstemmed | Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title_short | Regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| title_sort | regulation of neuronal genomic integrity through histone deacetylase cooperativity |
| topic | Brain and Cognitive Sciences. |
| url | http://hdl.handle.net/1721.1/110886 |
| work_keys_str_mv | AT dobbinmatthewmilnes regulationofneuronalgenomicintegritythroughhistonedeacetylasecooperativity |