Fernandez Cuesta, Cyntia (2024). Role of Uhrf1 and histone H3 ubiquitination in chromatin re-establishment during DNA replication. University of Birmingham. Ph.D.
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FernandezCuesta2024PhD.pdf
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Abstract
Chromatin re-establishment after DNA replication consists of nucleosome re-assembly and restoration of epigenetics marks in both daughter strands. These marks comprise DNA methylation and post-translational modifications of histones that regulate chromatin conformation and gene expression. Unrepaired errors during these processes result in genomic instability that leads to diseases such as cancer.
The E3 ubiquitin ligase Uhrf1 is an epigenetic regulator considered an oncogene for its ability to promote cell proliferation. This protein mediates DNA methylation maintenance by ubiquitinating histone H3 and Paf15 and subsequently recruiting DNA methyl transferase Dnmt1 to hemi-methylated sites. Although the role of Uhrf1 in recruiting Dnmt1 is clear, there are still many unresolved questions about the mechanism itself and how it is coordinated with other processes taking place at the same time, such as chromatin assembly and remodelling. This PhD project focuses on understanding the roles of Uhrf1 and histone H3 ubiquitination in DNA methylation maintenance and chromatin re-establishment during DNA replication.
Using Xenopus laevis egg extract as a model system, I have confirmed the role of Uhrf1 in mediating the dual mono-ubiquitination of histone H3 and Paf15 and recruiting Dnmt1 through ubiquitination. Importantly, this study has revealed that Uhrf1 also recruits Lig1 to replicating chromatin and its absence impairs the binding of Fen1 and CAF1. Finally, I have identified novel interacting partners of Uhrf1 during DNA replication. All these findings suggest that Uhrf1 plays a central and multifaceted role in chromatin-re-establishment, coordinating DNA methylation with DNA replication and nucleosome assembly.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (former) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Cancer and Genomic Sciences | |||||||||
| Funders: | Biotechnology and Biological Sciences Research Council | |||||||||
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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| URI: | http://etheses.bham.ac.uk/id/eprint/14924 |
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