Accurate chromosome segregation during mitosis and meiosis is critical for viability and development. Errors in chromosome segregation lead to aneuploidy, which is closely correlated with cancer. In order to ensure accurate chromosome segregation duplicated sister chromatids must be dramatically condensed and individualized upon entry into mitosis. Accurate chromosome distribution during mitosis depends on the interaction of duplicated sister chromatids with the microtubules of the mitotic spindle. Each chromosome contains one centromere that serves as the site for the formation of the kinetochore. At nuclear envelope breakdown, proteins important for kinetochore:microtubule (K:MT) attachment and signaling molecules that monitor K:MT attachment are recruited to the kinetochore. Successful completion of cell division requires the coordinated regulation of centromere/kinetochore assembly, kinetochore:microtubule attachment and chromosome condensation. Decades of work have identified hundreds of proteins that regulate various aspects of mitosis. However, very little is known about regulation of the transcriptome during mitosis. Recent work has demonstrated that remodeling of the transcriptome plays an important role in mitotic regulation. This proposal will study two fundamental aspects of transcriptome remodeling during mitosis. First, during mitosis, the majority of nuclear transcription is blocked, however, centromeres escape transcriptional down-regulation. Surprisingly, very little is known about the mechanism of transcriptional inhibition during mitosis or how disruption of mitotic transcriptional inhibition impacts the fidelity of chromosome segregation. It is also unknown if the process of mitotic transcriptional inhibition contributes to changing gene expression patterns. Second, during interphase hundreds to thousands of RNAs are retained in the nucleus where they bind to chromatin and regulate nuclear organization and gene expression. During mitosis many nuclear RNAs are released from chromatin, yet little is known about the mechanism of RNA removal from chromatin during mitosis. Additionally, it is unknown how disruption of RNA release from chromatin impacts the process of chromosome segregation or gene expression following mitosis. Our work will investigate how the transcriptome is remodeled during mitosis and how this contributes to accurate chromosome segregation.
The goal of this project is to understand how changes to the transcriptome facilitate accurate chromosome segregation during mitosis. These studies will provide fundamental insight into how cells segregate chromosomes during division, which will increase our understanding of the causes of cancer progression.
| Perea-Resa, Carlos; Blower, Michael D (2018) Centromere Biology: Transcription Goes on Stage. Mol Cell Biol 38: |
