Power of the chromosome
For accurate cell division, the genetic information in the DNA must be equally segregated into the two daughter cells. For this to happen, the chromatin compacts with the correct size, flexibility and rigidity. Furthermore, the sister chromatids from replication remain tightly associated with each other until anaphase starts. The CCC (Chromosome condensation and cohesion) project has investigated how dynamic mitotic chromosomes are assembled and how their morphology contributes to various aspects of mitosis. The team adopted a multidisciplinary approach combining acute protein inactivation, 4D-live cell imaging and biophysical/mathematical approaches to evaluate the role of chromosome condensation and sister chromatid cohesion in various aspects of mitotic fidelity. Using Drosophila embryos, the team investigated the role of condensin proteins in maintenance of chromosome structure. A TEV protease cleavage system was developed to inactivate condensin I systems. Unexpectedly, live cell imaging showed that condensin I inactivation caused over-condensation of the chromosome arms when the previously separated sister chromatids re-entwined and failed to segregate. The result was aneuploidy, an abnormal number of chromosomes. In collaboration with the Sullivan lab of the University of California, the CCC project showed the effect of accumulation of ectopic heterochromatin mediated by an increase in cohesion at pericentric heterochromatin within chromosome arms. In addition to identifying altered gene expression in neighbouring genes, the research indicates that mitotic errors may account for the disjoined chromatids during anaphase and significant chromosome stretching. From a medical point of view, these findings illustrate how chromosome rearrangements may snowball in their influence on the progress of mitosis and result in additional errors. Significantly, this may lead to the development of cancer. Problems with chromosome structural errors involved in mitosis should trigger the spindle assembly checkpoint (SAC) to halt mitosis. Work in conjunction with the Department of Biochemistry, University of Oxford has proposed that multiple feedback loops involving cyclin-dependent kinase 1 gradually impair error-correction efficiency in SAC due to cohesion loss. Understanding the ‘active chromosome’ and how chromosome morphology influences mitosis is pivotal to the understanding of mitotic defects and causes for aneuploidy. Not only does this impact changes in chromosome number but changes in length of regions of chromatin often observed in cancer cells.
Keywords
Chromosome, segregation, CCC, mitosis, aneuploidy, cancer
