Characterization of Gcn5 histone acetyltransferase in Schizosaccharomyces pombe

Abstract: The organisation of eukaryotic DNA into chromatin provides a natural barrier that prevents full access to the DNA thereby inhibiting events such as transcription, replication and repair. In order for these DNA-related events to occur, the chromatin needs to be modified by chromatin remodelling or, by reversible post-translational modifications. Histone acetylation is such a modification and is essential of numerous DNA related events. The enzymes involved in this event are conserved throughout evolution, underscoring their importance. This thesis describes the role of the conserved histone acetyltransferase (HAT) Gcn5 in transcriptional regulation in Schizosaccharomyces pombe. Here we show that Gcn5 plays an important role in stress response. We map genome-wide Gcn5 occupancy and show that Gcn5 is predominantly localized to coding regions of highly transcribed genes. We also map H3K14 acetylation during salt stress and show that Gcn5 collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. The interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation. We also investigate the interactions between Gcn5 and other histone deacetylases and acetyltransferases and show overlapping functionality between Gcn5 and another histone acetyltransferase, Mst2, in stress response, regulation of subtelomeric genes and DNA damage repair. Finally, we show that the role of Gcn5 in stress response is mediated by its catalytic activity and that its function in stress response is conserved among yeast species.