Functional interactions between chromatin modifying complexes and the nuclear pore in the yeast Saccharomyces cerevisiae

The nucleus is functionally organized by the arrangement of the chromosomes, the nuclear periphery, and spatial regulation of transcription. Though the nuclear periphery has been historically viewed as transcriptionally repressive, recent work in the budding yeast Saccharomyces cerevisiae has revealed that some genes physically relocate from the nuclear interior to the nuclear periphery upon transcriptional activation, where they associate with nuclear pore complexes (NPCs). This dissertation focuses on elucidating the mechanism and physiological significance of this phenomenon.;Our work reveals functional interactions between actively transcribed genes, chromatin modifying complexes, and the NPC. Specifically, we identify the SAGA histone acetyltransferase as a necessary link between the NPC and active GAL genes. Interestingly, this association requires the physical presence of SAGA rather than transcriptional activation by SAGA, suggesting that gene interaction with the NPC is mediated by protein-protein interactions between NPC subunits and transcriptional activators. Our studies also reveal that functional interactions between SAGA and the NPC regulate global transcript levels, particularly for highly transcribed genes. These findings suggest a role for NPC-gene interactions in regulating the global transcription of highly induced genes. In addition, we find that interactions between NPC and SAGA subunits are required for the retention of the GAL1 gene at the NPC, and defects in gene retention due to loss of NPC and SAGA subunits correlate with reduced ability of these cells to metabolize galactose. These findings suggest that gene relocation is comprised of two steps, recruitment and retention, and that gene relocation makes a significant contribution to transcriptional regulation. We also identify new factors potentially involved in gene relocation based on functional interactions between INO80 chromatin remodeling complex components and NPC subunits. Interestingly, we find that interactions between the NPC and INO80, as well as interactions between the NPC and SAGA, may play a role in DNA damage repair. These observations are consistent with a physiological role for relocation of damaged DNA to the NPC, analogous to relocation of transcribed genes. Taken together, these results suggest that the NPC is an important regulator of chromatin dynamics that promotes an open chromatin structure permissible to active DNA transactions.