HDACi-induced DNA damage: identifying potential endpoints for safety assessment

Wang, Wenbin 2016. HDACi-induced DNA damage: identifying potential endpoints for safety assessment. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Histone deacetylase inhibitors (HDACi) have been designed to alter the actions of epigenetic modifiers with the aim of 'reprogramming' the epigenome of diseased tissues back to their normal disease-free state. These inhibitors were designed to be non-DNA reactive and therefore considered safe from a genetic toxicology point of view. However, HDACi’s have been shown to induce DNA damage in healthy cells through unknown mechanisms, thereby posing significant risks to human health. Studies suggest that HDAC inhibitor-induced DNA damage is partly associated with changes in transcription and replication. Consequently, collisions between these events can result in the formation of DNA lesions and stable DNA:RNA hybrid structures (R-loops), which are implicated in the onset of cancer and various neurological diseases. Therefore, the aims of the current study were to better understand the mechanisms by which HDAC inhibitors may induce DNA damage and to identify potential endpoints for safety assessment: Chapter III: Efforts to study the effects of HDAC inhibition through a chemical approach proved unsuccessful in the yeast model organism but identified the HDAC mutant, rpd3Δ, showing histone hyper-acetylation compared to the wild type. Chapter IV: ChIP-chip was established for the TK6 lymphoblastoid cell line as a genome-wide tool for measuring the genotoxicity of HDAC inhibitors. Chapter V: Application of the ChIP-chip method showed that Trichostatin A-induced changes in histone H4 acetylation led to the re-distribution of transcription and replication on chromosome 17 in TK6 cells. This resulted in their co-localisation, suggestive of potential collisions. However, further efforts to determine this by mapping γH2AX and R-loop formation proved unsuccessful. Chapter VI: The yeast genetic mutant rpd3Δ was used to mimic the effects of treating with an HDAC inhibitor. The loss of RPD3 resulted in significantly higher levels of γH2A, predominantly at telomere regions. In conclusion, this thesis presents strong evidence to show that Trichostatin A promotes the co-localisation of transcription and replication, suggesting that there is a greater possibility of these processes colliding to form DNA damage.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit:	13 March 2017
Last Modified:	19 Oct 2019 02:34
URI:	https://orca.cardiff.ac.uk/id/eprint/98927

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