Abstract
[Truncated] This thesis describes the structural and functional characterisation of the Drosophila behaviour/human splicing (DBHS) protein family in a study that combines X-ray crystallography with solution scattering and complementary biophysical characterisation.
The DBHS protein family is something of an enigma, with reported functions in almost every step of gene regulation. Humans possess three DBHS paralogues; non-POU domain-containing octamer binding protein (NONO), paraspeckle protein component 1 (PSPC1) and splicing factor proline/glutamine rich (SFPQ),all of which share a highly conserved domain architecture. Since their discovery over two decades ago, the biological and clinical relevance of the family has undergone rapid development. Perturbing DBHS protein structure or abundance is strongly associated with the malignant progression of cancers such as neuroblastoma, intellectual disability in humans and broad transcriptional and post-transcriptional defects. As such, the DBHS proteins are a viable therapeutic target and/or prognostic marker. However, the mechanistic details of their function are unknown. Towards developing a molecular understanding of DBHS protein function, this study aimed to solve DBHS protein structures and complement the structures with an investigation into their RNA binding mechanisms.
The literature surrounding DBHS protein function has not been comprehensively reviewed in light of recent structural advances for well over a decade. Thus, the first part of this study presents a detailed literature review.Through an in-depth foray into the literature, the family are identified as dynamic proteins mediating a wide range of protein-protein and protein-nucleic acid interactions. As such, we describe them as a multipurpose molecular scaffold.
The DBHS protein family is something of an enigma, with reported functions in almost every step of gene regulation. Humans possess three DBHS paralogues; non-POU domain-containing octamer binding protein (NONO), paraspeckle protein component 1 (PSPC1) and splicing factor proline/glutamine rich (SFPQ),all of which share a highly conserved domain architecture. Since their discovery over two decades ago, the biological and clinical relevance of the family has undergone rapid development. Perturbing DBHS protein structure or abundance is strongly associated with the malignant progression of cancers such as neuroblastoma, intellectual disability in humans and broad transcriptional and post-transcriptional defects. As such, the DBHS proteins are a viable therapeutic target and/or prognostic marker. However, the mechanistic details of their function are unknown. Towards developing a molecular understanding of DBHS protein function, this study aimed to solve DBHS protein structures and complement the structures with an investigation into their RNA binding mechanisms.
The literature surrounding DBHS protein function has not been comprehensively reviewed in light of recent structural advances for well over a decade. Thus, the first part of this study presents a detailed literature review.Through an in-depth foray into the literature, the family are identified as dynamic proteins mediating a wide range of protein-protein and protein-nucleic acid interactions. As such, we describe them as a multipurpose molecular scaffold.
| Original language | English |
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| Qualification | Doctor of Philosophy |
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| Supervisors/Advisors |
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| Award date | 30 Aug 2016 |
| Publication status | Unpublished - 2016 |
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- THESIS - DOCTOR OF PHILOSOPHY - KNOTT Gavin John - 2016
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