Accurate segregation of chromosomes during cell division is critical to maintain the stability of the genome, and to prevent the development of numerous human diseases. One way that cells facilitate accurate chromosome segregation is by compacting their chromosomes into highly condensed structures before cell division. After cell division this compaction is reversed, which allows the genome to be accessible for other nuclear processes such as replication and transcription. The condensin complex mediates meiotic and mitotic chromosome condensation in all eukaryotes. However, the mechanisms that restrict condensin activity during the cell cycle remain a fundamental question that is not well understood. We recently discovered that cell cycle-regulated transcription and proteasomal degradation of a condensin subunit in budding yeast leads to its periodic expression, and that disrupting this regulation interferes with progression through the cell cycle. Interestingly, proteasomal regulation of condensin also occurs in metazoan cells, however the importance of this conserved mode of regulation is not well understood. The goal of this proposal is to determine how the periodic expression of condensin coordinates chromosome condensation with cell division.
In Aim 1 we will determine if yeast CAP-G is limiting for condensin complex formation in interphase cells, and elucidate pathways that regulate its proteasomal degradation.
In Aim 2, we will determine if constitutive expression of condensin delays the cell cycle by triggering genomic instability, causing checkpoint activation, or slowing progression through S- phase.
In Aim 3 we will use powerful molecular and genomic technologies to probe the three-dimensional structure of the yeast genome in different cell-cycle phases, and determine if constitutive expression or stabilization of condensin causes an increase in chromosome condensation in interphase cells. Together, these experiments will provide critical insight into how chromosome condensation is coordinated with cell division, and will reveal conserved mechanisms that regulate chromosome segregation in all eukaryotes.
Missegregation of chromosomes is the underlying cause of a number of developmental disorders and diseases such cancer. This project aims to understand how cells ensure accurate chromosome segregation, which will provide insight into how diseases arise, and may lead to new strategies for drug development.
|Mapa, Claudine E; Arsenault, Heather E; Conti, Michelle M et al. (2018) A balance of deubiquitinating enzymes controls cell cycle entry. Mol Biol Cell 29:2821-2834|
|Doughty, Tyler W; Arsenault, Heather E; Benanti, Jennifer A (2016) Levels of Ycg1 Limit Condensin Function during the Cell Cycle. PLoS Genet 12:e1006216|