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Title: The impact of the chromatin regulators, Abo1 and HIRA, on global nucleosome architecture
Author: Gál, Csenge
ISNI:       0000 0004 5919 7792
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2015
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HIRA is an evolutionarily conserved histone H3-H4 chaperone that mediates replication-independent nucleosome deposition and is important in a variety of contexts such as transcription, the response to DNA damage and cellular quiescence. Here the genome-wide contribution of HIRA to nucleosome organization in Schizosaccharomyces pombe was determined using a chromatin sequencing approach. Cells lacking HIRA (hip1Δ) experience a global reduction in nucleosome occupancy over the 3’ end of genes, consistent with the proposed role for HIRA in nucleosome re-assembly in the wake of RNA polymerase II. In addition, at HIRA-regulated promoters, it commonly maintains the proper occupancy of the -1 and +1 nucleosomes. Thus HIRA likely exerts its transcriptional regulatory roles through assembly/disassembly of specific target nucleosomes. In addition to transcription-coupled functions, HIRA has been implicated in the DNA damage response pathway. Indeed HIRA deficient cells present with increased sensitivity to DNA damaging agents and experience delays to the repair of DNA double strand breaks. Furthermore, hip1+ exhibits interactions with components of both the homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways. HIRA has also been identified as a regulator of nitrogen-starvation induced quiescence in S. pombe. Cells lacking HIRA are defective in both their ability to maintain and exit quiescence. Consistent with this, quiescent hip1Δ cells fail to properly induce MBF-dependent gene transcription in response to the restoration of a nitrogen source. During the course of this study Abo1, a bromodomain containing AAA-ATPase, was identified as a factor whose function potentially overlaps with histone chaperones such as HIRA. Therefore the contribution of Abo1 to global chromatin architecture was also assessed. Consistent with a nucleosome assembly function, abo1Δ cells have widespread changes to nucleosome occupancy and positioning in both euchromatic and heterochromatic regions of the genome. Furthermore, Abo1 physically interacts with the FACT histone chaperone and the distribution of Abo1 on chromatin is perturbed by loss of FACT subunits.
Supervisor: Not available Sponsor: Medical Research Council (MRC) ; National Institute for Health Research (NIHR)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available