Genomic DNA is compacted into a protein-DNA complex known as chromatin, which regulates diverse cellular processes including transcription, DNA replication, recombination, DNA repair and the maintenance of genome integrity. The structure and activity of chromatin is regulated by DNA sequences, histone variants, posttranslational histone modifications and chromatin remodelling complexes. Chromatin remodelling complexes are multi-subunit entities that contain a single core catalytic ATPase subunit able to generate an array of nucleosome-related outputs. Importantly, recent studies have revealed that genes of the SWI/SNF family of chromatin remodeling complexes are frequently mutated in diverse cancers; however, their functional contributions in tumourigenesis are largely unclear. This work is comprised of four major results chapters, examining the roles of targeting subunits of the RSC SWI/SNF complex in budding yeast and the homologous BAF180 tumour suppressor protein in mammalian cells. We identify novel functions for these proteins that are directly relevant to tumourigenesis. In the first section we explored the contributions of the two isoforms of the RSC SWI/SNF complex in DNA repair. We found that the two isoforms provide both overlapping and distinct functions in this process. In the second section we identify a novel function for BAF180 in promoting centromeric sister chromatid cohesion. Importantly, this defect was transcription-independent and represents a paradigm shift in the field of chromatin remodeling and cancer. In the third section we show that PBRM1 missense mutations identified in cancer samples specifically impair a cohesion-related subset of functions when expressed in budding yeast. Moreover, these mutations completely ablated centromeric cohesion in human cells. In the final section we report the findings that novel HDAC inhibitors, which constitute a promising class of anticancer drugs, selectively sensitize cells lacking BAF180. These significant results suggest that HDAC inhibitors could be important tools for the treatment of BAF180-deficient tumours.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:632787 |
| Date | January 2014 |
| Creators | Brownlee, Peter Moore |
| Publisher | University of Sussex |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://sro.sussex.ac.uk/id/eprint/51607/ |
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