Mechanisms of chromosomal instability

Abstract

Most solid tumors are aneuploid, having a chromosome number that is not a multiple of the haploid number, and many frequently mis-segregate whole chromosomes in a phenomenon called chromosomal instability (CIN). CIN positively correlates with poor patient prognosis, indicating that reduced mitotic fidelity contributes to cancer progression by increasing genetic diversity among tumor cells. Here, we review the mechanisms underlying CIN, which include defects in chromosome cohesion, mitotic checkpoint function, centrosome copy number, kinetochore-microtubule attachment dynamics, and cell-cycle regulation. Understanding these mechanisms provides insight into the cellular consequences of CIN and reveals the possibility of exploiting CIN in cancer therapy.

Figure 1. Chromosome segregation in mitosis

(A) Chromosomes associate with spindle microtubules following nuclear envelope breakdown. The spindle assembly checkpoint is responsible for preventing anaphase onset until all chromosomes form proper bi-oriented attachments to spindle microtubules. Destruction of cohesins permits sister chromatid separation to define anaphase. To ensure faithful chromosome segregation all sister chromatids must segregate to the same daughter cell. (B) Types of microtubule attachment. Correctly attached sister kinetochores orient toward opposite spindle poles (amphitely). Erroneous attachments include situations where only one kinetochore is attached to a spindle pole (monotely), both sister kinetochores are attached to the same pole (syntely), or one sister kinetochore is attached to both poles (merotely).

Figure 2. Lagging chromosomes in human melanoma

Anaphase cells in a hematoxylin-and-eosin-stained section of a human melanoma show lagging chromosomes (arrow) consistent with mitotic defects observed in cultured tumor cell lines. Image provided by Vincent Memoli (Department of Pathology, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center).

Figure 3. Formation and correction of merotelic kinetochore–microtubule attachments

Merotely arises in early mitosis in normal cells, but is efficiently corrected (lightning bolts) to establish proper bi-orientation needed for error-free chromosome segregation. Kinetochore–microtubule attachments in cancer cells with CIN are hyperstable, which reduces their intrinsic ability to correct merotelic attachments. Spindle assembly in cells with extra centrosomes progresses through transient multipolar intermediates that greatly increase the formation rate of merotelic attachments.