Chromosome Rearrangements, Glue and Cancer

October 09, 2014


Collaborators Raquel Oliveira (Gulbenkian Institute of Science) and Bill Sullivan (UCSC).


Chromosome pairs can be glued together in one, two or three places. However, having more than one of these connections can result in abnormal chromosome segregation (photo: Raquel Oliveira).

While investigating mechanisms that ensure that daughters of dividing cells receive a complete set of chromosomes, two collaborating labs—those of Bill Sullivan at UCSC and Raquel Oliveira at the Golbenkian Institute of Science, have discovered problems in these mechanisms that can lead to chromosome rearrangements, errors in cell division, and genetic stability—findings that suggest a previously unpredicted link to the development of cancers.

During division, each daughter cell must receive one and only one copy of each of the replicated chromosomes. A key mechanism maintaining the fidelity of this process is the presence of a cohesin complex—a kind of "molecular glue"—which holds the replicated chromosomes in their proper position until the final moment, when they are pulled to opposite poles. At this point, the glue is degraded, the bond between the chromosomes is broken and the chromosomes separate into the newly formed daughter cells. The molecular glue is positioned in a region of the chromosome that contains highly repeated sequences, known as centromeric heterochromatin. Whether the heterochromatin plays a role in positioning and timing of cohesin degradation has been a major question in the field.

The Sullivan lab at UCSC and Oliveira lab at Portugal's Golbenkian Institute of Science directly addressed this issue by testing several strains of the fruit fly, Drosophila melanogaster, which carry chromosomal rearrangements in which long stretches of heterochromatin from near the centromere have been misplaced within distant euchromatic regions. They found that such inappropriately located heterochromatin is enough to promote increased levels of cohesin complex loading and the formation of additional constrictions, regardless of proximity to the centromere. Importantly, they also showed that, as cell division proceeds and the sister chromatids move to opposite poles of the cell, the presence of ectopic heterochromatin (and hence ectopic cohesin) leads to significant chromosome stretching, due to impaired resolution of the ectopic cohesin sites. These results highlight the possibility that chromosome rearrangements involving heterochromatin regions near the centromeres can induce additional errors in cell division and thereby compromise genetic stability.

It is well established that chromosome rearrangements associated with specific cancers are the result of dramatic alterations in the coding and regulatory regions of specific genes. The work by the Oliveira and Sullivan labs suggests an unexpected additional possibility: a subset of these rearrangements disrupt the ability of partner chromosomes to segregate during cell division. Like a car with its engine out of tune, over many cell divisions, this is likely to result in the severe disruptions in chromosome organization found in cancer cells.

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