Aldous, Sarah Grace;
(2019)
S-Nitrosylation of the NuRD Complex in Cortical Neurons.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The Nucleosome Remodelling and Histone Deacetylation (NuRD) complex is a chromatin remodeling complex that couples ATP-dependent nucleosome sliding with histone deacetylase activity. Despite playing an essential role during neuronal differentiation and cortical development, the mechanism regulating NuRD complex formation and specificity remains unknown. The aim of my project was to investigate whether S-nitrosylation of the NuRD subunits affects their function. S-nitrosylation (SNO) is the addition of a nitrosyl (NO) group to cysteine thiols. Both NO signalling and specific SNO-protein modifications are known to regulate the expression of genes necessary for neuronal development and migration. A recent screen in our laboratory aimed at identifying S-nitrosylated nuclear proteins in cortical neurons revealed that most subunits of the NuRD complex undergo S-nitrosylation. I investigated the functional relevance of this modification for the NuRD subunit Retinoblastoma binding protein 7 (RBBP7) and identified the nitrosylated cysteine residue. My data indicate that S-nitrosylation of Cys166 regulates RBBP7 interaction with the Chromodomain helicase DNA binding protein 4 (CHD4) subunit and promotes activity-dependent dendritic growth. I also found that the three ATPase CHD3, CHD4 and CHD5 are targets of S-nitrosylation. I have also characterised a lysine containing motif required for specific target S-nitrosylation. Overall my work demonstrates the widespread role of S-nitrosylation in regulating nuclear functions and provides the first evidence that NO links extrinsic signals to NuRD-dependent chromatin modifications.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | S-Nitrosylation of the NuRD Complex in Cortical Neurons |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | S-Nitrosylation, Chromatin Remodelling |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10065622 |
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