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Understanding mechanisms of mitotic nuclear envelope reassembly using inducible relocalisation strategies
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Downie, Laura (2023) Understanding mechanisms of mitotic nuclear envelope reassembly using inducible relocalisation strategies. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3973294
Abstract
Cell division involves the accurate segregation of chromosomes to two daughter cells by the mitotic spindle. Errors in this process can lead to developmental defects or diseases, including cancers. During mitosis, the mitotic spindle is within an “exclusion zone” (EZ) from which membrane structures are mostly absent. Polar misaligned chromosomes may be positioned in the region containing densely packed endomembranes outside of the EZ. Recent work in our lab has shown that these misaligned chromosomes can become wrapped in multiple layers of endomembranes, and that this promotes aneuploidy fate and micronucleus (MN) formation. The envelope assembled at misaligned chromosomes forming MN provides insufficient protection of the micronuclear DNA. The MN envelope is also unstable and prone to rupture, which exposes the micronuclear DNA to cytoplasmic content and can result in extensive DNA damage and propagate chromosomal instability. Our main aim is to understand the NE reassembly mechanism, particularly the recruitment of NE proteins and membranes to chromatin, which will inform how this process is defective at missegregated chromosomes forming MN. Key to this is understanding the organisation of nuclear components after nuclear envelope breakdown in early mitosis. We have developed methods to induce the relocalisation of membrane compartments and key proteins of NE reassembly in live cells. This unexpectedly revealed distinct behaviours of different proteins originating from the NE to that of a marker of the ER during mitosis. Ultrastructural analysis of relocalised compartments provided clear evidence in support of the presence of subdomains within the ER enriched in particular profiles of NE proteins. Our functional data suggest a role for these subdomains in NE reassembly and we propose that concentrating proteins within these subdomains makes the reassembly process more efficient.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics |
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Library of Congress Subject Headings (LCSH): | Cell division, Nuclear membranes, Mitosis, Nucleolus, Chromosomes abnormalities, Aneuploidy | ||||
Official Date: | January 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Royle, Stephen J. | ||||
Sponsors: | Biotechnology and Biological Sciences Research Council (Great Britain) | ||||
Format of File: | |||||
Extent: | multiple pageings : illustrations | ||||
Language: | eng |
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