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Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy. / Sion Bayliss

Swansea University Author: Sion Bayliss

Abstract

The research described in this thesis aimed to evaluate the intrinsic DNA curvature ofthe region of the TP53 tumour suppressor gene that codes for the sequence-specific DNA-binding domain of the p53 protein, a key protein that protects the cell from chemical insultsand tumourogenesis. There have bee...

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Published: 2012
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42829
first_indexed 2018-08-02T18:55:38Z
last_indexed 2019-10-21T16:48:32Z
id cronfa42829
recordtype RisThesis
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spelling 2018-08-29T14:28:32.6500579 v2 42829 2018-08-02 Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy. 3c4691ebe62d490228f443bdd358444b NULL Sion Bayliss Sion Bayliss true true 2018-08-02 The research described in this thesis aimed to evaluate the intrinsic DNA curvature ofthe region of the TP53 tumour suppressor gene that codes for the sequence-specific DNA-binding domain of the p53 protein, a key protein that protects the cell from chemical insultsand tumourogenesis. There have been no previous attempts to experimentally investigate theintrinsic DNA curvature within TP53 or its relation to the functional or structural properties ofthe gene, such as DNA repair and nucleosomal architecture. The present study usedtheoretical models of TP53 in concert with an atomic force microscopy based experimentalinvestigation of TP53 DNA molecules to analyse intrinsic DNA curvature within the gene. Thiswas achieved by developing a novel software platform for the atomic force microscopy basedinvestigation of DNA curvature, named ADIPAS. Dinucleotide wedge models of DNA curvaturewere used to model TP53 in order to investigate the relationship between intrinsic DNAcurvature and the structure and function of the gene. ADIPAS was applied to atomic forcemicroscopy images of TP53 DNA molecules immobilised on a mica surface in order toexperimentally measure intrinsic DNA curvature. The experimental findings were compared totheoretical models of intrinsic curvature in TP53. The resulting intrinsic curvature profilesshowed that exons exhibited significantly lower intrinsic DNA curvature than introns withinTP53, this was also shown to be true for regions of slow DNA repair. This indicated that DNAcurvature may play a role in TP53 as a controlling factor for nucleosomal architecture tofacilitate open chromatin and active DNA transcription. The evolutionary selection for intrinsiccurvature may have played a role in the development of exons with low intrinsic DNAcurvature. Low intrinsic curvature in exon position has also been implicated in the reducedefficiency of DNA repair in a number of cancer specific mutation hotspots. E-Thesis DNA binding 31 12 2012 2012-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T14:28:32.6500579 2018-08-02T16:24:30.5701964 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Sion Bayliss NULL 1 0042829-02082018162525.pdf 10821219.pdf 2018-08-02T16:25:25.1570000 Output 27343803 application/pdf E-Thesis true 2018-08-02T16:25:25.1570000 false
title Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
spellingShingle Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
Sion Bayliss
title_short Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
title_full Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
title_fullStr Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
title_full_unstemmed Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
title_sort Analysis of intrinsic DNA curvature in the TP53 tumour suppressor gene using atomic force microscopy.
author_id_str_mv 3c4691ebe62d490228f443bdd358444b
author_id_fullname_str_mv 3c4691ebe62d490228f443bdd358444b_***_Sion Bayliss
author Sion Bayliss
author2 Sion Bayliss
format E-Thesis
publishDate 2012
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description The research described in this thesis aimed to evaluate the intrinsic DNA curvature ofthe region of the TP53 tumour suppressor gene that codes for the sequence-specific DNA-binding domain of the p53 protein, a key protein that protects the cell from chemical insultsand tumourogenesis. There have been no previous attempts to experimentally investigate theintrinsic DNA curvature within TP53 or its relation to the functional or structural properties ofthe gene, such as DNA repair and nucleosomal architecture. The present study usedtheoretical models of TP53 in concert with an atomic force microscopy based experimentalinvestigation of TP53 DNA molecules to analyse intrinsic DNA curvature within the gene. Thiswas achieved by developing a novel software platform for the atomic force microscopy basedinvestigation of DNA curvature, named ADIPAS. Dinucleotide wedge models of DNA curvaturewere used to model TP53 in order to investigate the relationship between intrinsic DNAcurvature and the structure and function of the gene. ADIPAS was applied to atomic forcemicroscopy images of TP53 DNA molecules immobilised on a mica surface in order toexperimentally measure intrinsic DNA curvature. The experimental findings were compared totheoretical models of intrinsic curvature in TP53. The resulting intrinsic curvature profilesshowed that exons exhibited significantly lower intrinsic DNA curvature than introns withinTP53, this was also shown to be true for regions of slow DNA repair. This indicated that DNAcurvature may play a role in TP53 as a controlling factor for nucleosomal architecture tofacilitate open chromatin and active DNA transcription. The evolutionary selection for intrinsiccurvature may have played a role in the development of exons with low intrinsic DNAcurvature. Low intrinsic curvature in exon position has also been implicated in the reducedefficiency of DNA repair in a number of cancer specific mutation hotspots.
published_date 2012-12-31T04:25:35Z
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score 11.096068

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