Roles of histone deacetylases and histone phosphorylation in transcription and nucleotide excision repair in Saccharomyces cerevisiae.

O'Connell, Charlotte. 2007. Roles of histone deacetylases and histone phosphorylation in transcription and nucleotide excision repair in Saccharomyces cerevisiae. PhD Thesis, Cardiff University.

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Abstract

Repair of UV-induced damage in the cell is crucial to maintain genome integrity and stability. Acetylation of the histone ammo-terminal tails plays key roles in transcription and DNA repair pathways. Acetylation states are determined by a balance between the activities of histone acetyltransferases (HATs) and histone deacerylases (HDACs). This study examined the roles of histone deacetylation in transcription and nucleotide excision repair (NER) in Saccharomyces cerevisiae using mutant strains defective in one or more of the genes encoding the deacetylases Rpd3, Hdal, Hosl, Hos2 and Hos3. Single mutations in the genes RPD3 and HDA1 and the various tested combinations of triple mutations did not cause any detectable loss of transcriptional repression of the model MFA2 gene. rpd3 and hdal mutants were not found to confer a significant change in sensitivity to UV radiation, however all triple mutations tested resulted in increased UV sensitivity of the cells. Examination of the removal of UV-induced cyclobutane pyrimidine dimers from the genome overall revealed that combined mutations in RPD3, HOS1 and HOS2 or in RPD3, HOS1 and HDA1 resulted in enhanced NER, which intriguingly appears to contradict the UV sensitivity effects. Enhanced NER was also observed at the repressed MFA2 gene for the same triple mutations, indicating roles for the histone deacetylase genes in chromatin alteration during both global and local NER. The NER effects were only observed upon deletion of multiple genes, suggesting a degree of functional redundancy among the deacetylase proteins. Increasing evidence for an epigenetic histone code and interplay between post-translational histone modifications led to speculation that histone phosphorylation may also play a role in NER. Increased UV sensitivity was conferred by specific mutations in the tails of histone H2A and H2B. Genome-wide analysis in a histone mutant with the H2B tail truncated at serine position 125 suggested that any roles for this site in NER are likely to be specific to certain regions of the genome rather than involved in global NER.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303174704
Date of First Compliant Deposit:	30 March 2016
Last Modified:	08 May 2019 02:51
URI:	https://orca.cardiff.ac.uk/id/eprint/54298

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