CCC · Chromosome Condensation and Cohesion

Accurate cell division relies on the fact that the genetic information encoded in the DNA molecules is equally segregated into the two daughter cells. Proper partitioning of the genome, in turn, depends on two key changes in chromosome organization: 1) chromatin is converted into compact structures with the right mechanical properties (size, flexibility, rigidity) to facilitate their segregation; 2) the two sister DNA molecules remain tightly associated with each other from the moment of DNA replication until the metaphase-anaphase transition of the subsequent mitosis. Although chromosomes were long assumed to play rather a passive role during the cell division process, recent evidence suggests that chromosomes play a much more active role in the process of their own segregation. Understanding the “active chromosome” and how chromosome morphology influences mitosis is pivotal to the understanding of novel routes to mitotic defects and causes for aneuploidy. Here I propose to investigate how dynamic mitotic chromosomes are assembled and how their morphology contributes to various aspects of mitosis. I plan to use a multidisciplinary approach, combining acute protein inactivation, 4D-live cell imaging and biophysical/mathematical approaches to evaluate role of condensin complexes, one of the most abundant non-histone chromosomal proteins, in the process of chromosome assembly. In addition, I propose to investigate how chromosome condensation and cohesion influence the dynamics of chromosome segregation and how (if) cells adapt when in the presence of abnormal chromosomes. I will develop experimental conditions to mimic different degrees of “cohesion fatigue” (partial loss of sister chromatid cohesion), as well as a variety of abnormalities in chromosome structure and size and quantitatively evaluate how chromosome cohesion and condensation influence chromosome dynamics and signaling of the surveillance mechanism that control mitosis (the Spindle Assembly Checkpoint).