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dc.contributor.advisorDodson, Helen
dc.contributor.advisorFlaus, Andrew
dc.contributor.advisorDockery, Peter
dc.contributor.authorPassos, Joana
dc.date.accessioned2020-02-14T09:16:08Z
dc.date.issued2019-12-09
dc.identifier.urihttp://hdl.handle.net/10379/15784
dc.description.abstractHistones are responsible for the packaging of DNA into a eukaryotic cell nucleus, and the H2A variant H2AX plays an important role in the DNA damage response (DDR). The phosphorylated form of H2AX, known as γH2AX, has been suggested as a prognostic cancer biomarker although it is unclear how variations in H2AFX copy number, mRNA and protein abundance contribute to genome instability. Analysis of copy number alterations (CNAs) in large human cancer datasets has revealed that H2AFX seldom undergoes amplification or homozygous deletions and is rarely mutated. In contrast, loss of one copy of H2AFX is very common and 41% of samples in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset exhibit loss of one H2AFX allele. This loss is most frequent in the hormone receptor positive luminal B subtype (LumB, 63%), which is characterised by rapid cell proliferation, genome instability and overall poor prognosis. No homozygous deletions or mutations of H2AFX are observed in LumB tumours and only 2% of samples show H2AFX amplifications, suggesting that H2AFX could be essential. Four cell lines which represent H2AFX copy number status and luminal subtypes were selected from the Cancer Cell Line Encyclopaedia (CCLE) to investigate the effects of loss of one H2AFX allele. This revealed that H2AFX CNAs have little impact on transcript or protein abundance. Measurement of γH2AX foci formation and disappearance after ionising irradiation show that H2AX is rapidly phosphorylated after damage and repair is facilitated without correlation to the molecular subtype or H2AFX gene dosage. In summary, we propose that H2AFX is essential in breast cancer but that loss of one H2AFX allele is well tolerated and leaves near-normal abundance of mRNA and protein. This suggests a regulatory mechanism to maintain H2AX abundance and a robust DDR irrespective of H2AFX copy number or breast cancer subtype.en_IE
dc.publisherNUI Galway
dc.subjectbreast canceren_IE
dc.subjectH2AXen_IE
dc.subjectcopy number variationen_IE
dc.subjectDNA damage responseen_IE
dc.subjectDNA double strand breaksen_IE
dc.subjectMedicineen_IE
dc.subjectAnatomyen_IE
dc.titleImplications of histone H2AX abundance in breast canceren_IE
dc.typeThesisen
dc.contributor.funderIrish Research Councilen_IE
dc.contributor.funderCollege of Medicine, Nursing and Health Sciences, National University of Ireland Galwayen_IE
dc.contributor.funderAnatomy Department, School of Medicine, National University of Ireland Galwayen_IE
dc.local.noteHistone proteins are responsible for the packaging of DNA into a eukaryotic cell nucleus, and the H2A variant H2AX plays an important role in the DNA damage response. This thesis investigates how alterations in H2AFX copy number, mRNA expression and protein abundance contribute to genome instability in breast cancer.en_IE
dc.description.embargo2021-02-12
dc.local.finalYesen_IE
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