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Title: Investigating the function of the human homologue of Caenorhabditis elegans Mau-2
Author: Seitan, Vlad Cezar
ISNI:       0000 0001 3393 2670
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2008
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Eukarjotic chromosome segregation requires that sister chromatids are kept in close association from the time of their generation (S-phase) until anaphase, a phenomenon known as sister chromatid cohesion. The structural basis of cohesion is a highly conserved heteromeric complex called cohesin and sister chromatid cohesion is regulated through controlled cycles of chromatin-association and dissociation of this complex. Cohesin is loaded onto chromatin before replication, a process that in budding yeast requires a separate complex containing the proteins Scc2 and Scc4. Scc2 is very highly conserved and homologues have been identified in all eukaryotic species. Consistent with the strong evolutionary conservation, Scc2 homologues have preserved their chromosomal function. In addition, metazoan Scc2 appear to have acquired new roles in gene regulation and development. The Drosophila homologue, Nipped-B, is known as a general factor that facilitates the interaction between promoters and their remote enhancers, while the gene encoding human Scc2, NIPBL, is mutated in the developmental disorder Cornelia de Lange Syndrome. In contrast to Scc2, its fungal partner Scc4 is very poorly conserved. Prior to this study, no homologues of this protein were known outside a small group of yeast that are very closely related to Saccharomyces cerevisiae. This case is unique among proteins in the sister chromatid cohesion pathway (which are all very highly conserved among eukaryotes) consequently casting doubt over the conservation of the cohesin loading machinery. The study presented here shows that the previously uncharacterised human protein KLl\A0892 is evolutionarily and functionally related to S. cerevisiae Scc4. KlAA0892 binds to delangin and PSI-BLAST reveals that it is a distant homologue of Scc4. KlAA0892 is required for the loading of cohesin onto chromatin and its depletion from Hela cells leads to increased premature centromere separation, indicating that it is also a functional homologue of Scc4. Similarly to Scc2, metazoan Scc4 also seem to have acquired roles in development, as nematode orthologues have previously been implicated in cell and axon migration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available