Investigating protein-protein interactions of the Bloom Syndrome complex
<p>Bloom Syndrome is a rare recessive chromosomal instability disorder, caused by loss-of-function mutations in the BLM helicase tumour suppressor. Patients develop a variety of developmental defects and have an increased predisposition to all cancers.</p> <p>BLM interacts with T...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1797101459515375616 |
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| author | Belblidia, Z |
| author2 | Blackford, A |
| author_facet | Blackford, A Belblidia, Z |
| author_sort | Belblidia, Z |
| collection | OXFORD |
| description | <p>Bloom Syndrome is a rare recessive chromosomal instability disorder, caused by loss-of-function mutations in the BLM helicase tumour suppressor. Patients develop a variety of developmental defects and have an increased predisposition to all cancers.</p>
<p>BLM interacts with TOP3A, RMI1 and RMI2 to form the BTR complex, which functions to promote the restart of stalled forks and the dissolution of double Holliday junctions during
homologous recombination repair to the prevent the formation of sister chromatid exchanges. </p>
<p>Since most patient mutations abrogate all of BLM’s functions, it is unknown which specific function(s) are important for tumour suppression. Moreover, the functions of the unstructured
regions are poorly defined. To address this, I aim to identify and characterize separation-of-function mutations within conserved motifs of the unstructured regions of the BTR complex. </p>
<p>Firstly, I identified several RPA binding motifs in BLM and RMI1 which are important for cellular resistance to HU but are not important the dissolution of dHJs. Secondly, I found that
highly conserved FTF residues within the N-terminus of BLM are important for interactions with TOP3A, RMI1 and RMI2, which are partially functional in resistance to hydroxyurea treatment and suppression of sister chromatid exchanges. Thirdly, I found that conserved residues within the N-terminal dimerization helical bundle are important for BLM dimerization and that these residues are partially functional for resistance to HU treatment and suppression of sister chromatid exchanges. </p>
<p>My results demonstrate that there are several conserved unstructured motifs in BLM that mediate specific protein-protein interactions. Furthermore, my data proposes several models
of how these motifs and interactions regulate several cellular functions of the BTR complex.
This work may provide a future insight into which specific cellular functions of BLM are important for preventing tumorigenesis in future animal models in which the conserved regions we have studied are mutated. </p>
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| first_indexed | 2024-03-07T05:52:15Z |
| format | Thesis |
| id | oxford-uuid:e948ce1b-93ec-4950-9649-91f1a13940f4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:52:15Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:e948ce1b-93ec-4950-9649-91f1a13940f42022-03-27T10:53:11ZInvestigating protein-protein interactions of the Bloom Syndrome complexThesishttp://purl.org/coar/resource_type/c_bdccuuid:e948ce1b-93ec-4950-9649-91f1a13940f4EnglishHyrax Deposit2021Belblidia, ZBlackford, A<p>Bloom Syndrome is a rare recessive chromosomal instability disorder, caused by loss-of-function mutations in the BLM helicase tumour suppressor. Patients develop a variety of developmental defects and have an increased predisposition to all cancers.</p> <p>BLM interacts with TOP3A, RMI1 and RMI2 to form the BTR complex, which functions to promote the restart of stalled forks and the dissolution of double Holliday junctions during homologous recombination repair to the prevent the formation of sister chromatid exchanges. </p> <p>Since most patient mutations abrogate all of BLM’s functions, it is unknown which specific function(s) are important for tumour suppression. Moreover, the functions of the unstructured regions are poorly defined. To address this, I aim to identify and characterize separation-of-function mutations within conserved motifs of the unstructured regions of the BTR complex. </p> <p>Firstly, I identified several RPA binding motifs in BLM and RMI1 which are important for cellular resistance to HU but are not important the dissolution of dHJs. Secondly, I found that highly conserved FTF residues within the N-terminus of BLM are important for interactions with TOP3A, RMI1 and RMI2, which are partially functional in resistance to hydroxyurea treatment and suppression of sister chromatid exchanges. Thirdly, I found that conserved residues within the N-terminal dimerization helical bundle are important for BLM dimerization and that these residues are partially functional for resistance to HU treatment and suppression of sister chromatid exchanges. </p> <p>My results demonstrate that there are several conserved unstructured motifs in BLM that mediate specific protein-protein interactions. Furthermore, my data proposes several models of how these motifs and interactions regulate several cellular functions of the BTR complex. This work may provide a future insight into which specific cellular functions of BLM are important for preventing tumorigenesis in future animal models in which the conserved regions we have studied are mutated. </p> |
| spellingShingle | Belblidia, Z Investigating protein-protein interactions of the Bloom Syndrome complex |
| title | Investigating protein-protein interactions of the Bloom Syndrome complex |
| title_full | Investigating protein-protein interactions of the Bloom Syndrome complex |
| title_fullStr | Investigating protein-protein interactions of the Bloom Syndrome complex |
| title_full_unstemmed | Investigating protein-protein interactions of the Bloom Syndrome complex |
| title_short | Investigating protein-protein interactions of the Bloom Syndrome complex |
| title_sort | investigating protein protein interactions of the bloom syndrome complex |
| work_keys_str_mv | AT belblidiaz investigatingproteinproteininteractionsofthebloomsyndromecomplex |