Twenty years of merotelic kinetochore attachments: a historical perspective

Abstract

Micronuclei, small DNA-containing structures separate from the main nucleus, were used for decades as an indicator of genotoxic damage. Micronuclei containing whole chromosomes were considered a biomarker of aneuploidy and were believed to form, upon mitotic exit, from chromosomes that lagged behind in anaphase as all other chromosomes segregated to the poles of the mitotic spindle. However, the mechanism responsible for inducing anaphase lagging chromosomes remained unknown until just over twenty years ago. Here, I summarize what preceded and what followed this discovery, highlighting some of the open questions and opportunities for future investigation.

Keywords: chromosome segregation; lagging chromosome; merotelic; micronuclei; mitosis.

Figure 1.

Diagram showing formation of micronuclei upon mitotic exit. Chromosomes/DNA are depicted in blue, kinetochores in orange. A. Formation of a kinetochore-negative micronucleus from a lagging chromosome fragment. B. Formation of a kinetochore-positive micronucleus from an anaphase lagging chromosome. C. Formation of a kinetochore-positive micronucleus in a binucleate cell in the cytokinesis-block assay.

Figure 2.

Fate of anaphase lagging chromosomes depends on the relative size of the microtubule bundles connecting the merotelic kinetochore to the two spindle poles. A. Example of live cell (top) and diagram (middle) of a “balanced” merotelically attached anaphase lagging chromosome. In the images (taken two minutes apart), the lagging kinetochore can be seen persisting at the cell equator as all the other chromosomes move poleward. As a result of this, a whole chromosome-containing micronucleus is formed in one of the daughter cells (bottom). B. Example of live cell (top) and diagram (middle) of an “unbalanced” merotelically attached anaphase lagging chromosome. In the images (taken three minutes apart), two merotelically attached kinetochores can be seen. However, because of the different size of the two microtubule bundles connecting the merotelic kinetochores to the two spindle poles, the chromosomes’ position is shifted close to the group of normally segregating chromosomes on the right. As a result of this, the chromosome(s) will be included in the main nucleus in one of the daughter cells (bottom). In the images, kinetochores are in green and microtubules are red. In the diagrams, chromosomes/DNA are depicted in blue, kinetochores in orange. Live cell images are modified from Cimini et al., 2004 (A) and Cimini et al., 2006 (B).