Identification of novel DNA damage response mechanisms using SLiM proteomics
<p>The repair of damaged DNA is essential for maintaining genome integrity. Accordingly, all known forms of life have evolved a complex repertoire of biochemical pathways to detect and repair such damage, collectively called the DNA damage response. Like all biological pathways, the DNA damage...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2022
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| _version_ | 1826310534965755904 |
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| author | Shorrocks, A-MK |
| author2 | Blackford, A |
| author_facet | Blackford, A Shorrocks, A-MK |
| author_sort | Shorrocks, A-MK |
| collection | OXFORD |
| description | <p>The repair of damaged DNA is essential for maintaining genome integrity. Accordingly, all known forms of life have evolved a complex repertoire of biochemical pathways to detect and repair such damage, collectively called the DNA damage response. Like all biological pathways, the DNA damage response is facilitated by a series of protein-protein interactions, but the mechanisms by which DNA repair protein complexes are assembled, disassembled and regulated by post-translational modifications are still poorly understood.</p>
<p>To address this issue, a combined bioinformatics and proteomics approach was developed to identify and characterize novel protein-protein interactions in DNA damage response proteins relying on Short Linear peptide Motifs (SLiMs). Using this approach, novel interactions have been identified between the DNA repair proteins: MDC1 and TOPBP1, TOPBP1 and CIP2A, AUNIP and CtIP, and between the BLM helicase complex and the single-stranded DNA binding protein RPA. Investigation of the functional relevance of the interaction between the BLM helicase complex and RPA demonstrated that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and replication fork restart.</p>
<p>To overcome the limitations of manually identifying SLiMs, a web-based tool was developed to predict SLiMs in DDR proteins automatically. This work forms the foundation for the development of a DNA repair interactome based on SLiMs, for a greater understanding of the diverse range of pathologies associated with mutations in DNA repair genes and the development of new therapies.</p> |
| first_indexed | 2024-03-07T07:53:25Z |
| format | Thesis |
| id | oxford-uuid:b8d401bf-d597-4297-a2e1-75b4e29e8366 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:53:25Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:b8d401bf-d597-4297-a2e1-75b4e29e83662023-07-27T07:59:33ZIdentification of novel DNA damage response mechanisms using SLiM proteomicsThesishttp://purl.org/coar/resource_type/c_db06uuid:b8d401bf-d597-4297-a2e1-75b4e29e8366EnglishHyrax Deposit2022Shorrocks, A-MKBlackford, A<p>The repair of damaged DNA is essential for maintaining genome integrity. Accordingly, all known forms of life have evolved a complex repertoire of biochemical pathways to detect and repair such damage, collectively called the DNA damage response. Like all biological pathways, the DNA damage response is facilitated by a series of protein-protein interactions, but the mechanisms by which DNA repair protein complexes are assembled, disassembled and regulated by post-translational modifications are still poorly understood.</p> <p>To address this issue, a combined bioinformatics and proteomics approach was developed to identify and characterize novel protein-protein interactions in DNA damage response proteins relying on Short Linear peptide Motifs (SLiMs). Using this approach, novel interactions have been identified between the DNA repair proteins: MDC1 and TOPBP1, TOPBP1 and CIP2A, AUNIP and CtIP, and between the BLM helicase complex and the single-stranded DNA binding protein RPA. Investigation of the functional relevance of the interaction between the BLM helicase complex and RPA demonstrated that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and replication fork restart.</p> <p>To overcome the limitations of manually identifying SLiMs, a web-based tool was developed to predict SLiMs in DDR proteins automatically. This work forms the foundation for the development of a DNA repair interactome based on SLiMs, for a greater understanding of the diverse range of pathologies associated with mutations in DNA repair genes and the development of new therapies.</p> |
| spellingShingle | Shorrocks, A-MK Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title | Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title_full | Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title_fullStr | Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title_full_unstemmed | Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title_short | Identification of novel DNA damage response mechanisms using SLiM proteomics |
| title_sort | identification of novel dna damage response mechanisms using slim proteomics |
| work_keys_str_mv | AT shorrocksamk identificationofnoveldnadamageresponsemechanismsusingslimproteomics |