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Title: S-Nitrosylation of the NuRD complex in cortical neurons
Author: Aldous, Sarah Grace
ISNI:       0000 0004 7660 3553
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Riccio, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available