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Title: Deciphering tetraploid tolerance
Author: Crockford, Andrew
ISNI:       0000 0004 7229 874X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Chromosomal instability and aneuploidy are common features of human malignancies, which fuel genetic heterogeneity and can lead to inaccurate diagnosis and treatment failure. Tetraploidy has been shown as an intermediate of aneuploidy and, thus, understanding the molecular mechanisms governing tetraploid tolerance is of great importance. A frequent tolerance mechanism observed in experimental systems and human tumours is loss of TP53, highlighting its central role in the tetraploidy checkpoint. However, despite this association, more than half of genome-doubled tumours are TP53 wild-type. The aim of this project was to understand how tetraploid cells could tolerate the polyploidy phenotype with a functional p53/p21 axis. Firstly, tetraploidy tolerance was investigated in an isogenic HCT-116 diploid and tetraploid system. The HCT-116 tetraploids showed functional p53, in response to DNA damage and segregation error induction, while also displayed elevated basal level of both proteins. Despite this, the tetraploid clones could proliferate and showed no evidence of cell cycle arrest, suggesting the p53/p21 tetraploidy checkpoint response had been overridden. Quantitative proteomics revealed cyclin D1 overexpression in the tetraploid clones. As cyclin D1 can sequester p21, their relationship was investigated and validated in the HCT-116 system. To further test if elevated cyclin D1 could affect tolerance, cytokinesis failure was pharmacologically induced in RPE cells, where cyclin D1 overexpression promoted tetraploidy tolerance across multiple assays. In addition, bioinformatics analysis revealed that D-type cyclins were overexpressed in TP53, CDKN1A and RB1 wild-type, genome-doubled testicular germ cell tumours (TGCT). These findings indicate that D-type cyclin overexpression can provide tetraploidy tolerance in vitro and may be implicated in TGCT genome-doubling and pathogenesis.
Supervisor: Swanton, Charles Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available