Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression

Abstract

Errors in chromosome segregation during mitosis have been recognized as a hallmark of tumor cells since the late 1800s, resulting in the long-standing hypothesis that mitotic abnormalities drive tumorigenesis. Recent work has shown that mitotic defects can promote tumors, suppress them, or do neither, depending on the rate of chromosome missegregation. Here we discuss the causes of chromosome missegregation, their effects on tumor initiation and progression, and the evidence that increasing the rate of chromosome missegregation may be an effective chemotherapeutic strategy.

Keywords: CIN; aneuploidy; chromosomal instability; mitosis; mitotic checkpoint; spindle assembly checkpoint.

Figure 1. Causes of chromosome missegregation

(A) A normal mitosis in which sister chromatid pairs make amphitelic attachments (in which one sister chromatid is attached to each spindle pole) produces two genetically identical daughter cells. (B) Weakened mitotic checkpoint signaling permits cells to enter anaphase before each sister chromatid pair has made stable attachments to both spindle poles, resulting in chromosome missegregation. (C–D) Chromatids that lag behind the segregating masses of DNA (lagging chromosomes) represent another source of mitotic errors. (C) Incorrect kinetochore-microtubule attachments, such as merotelic attachments in which a single kinetochore is attached to microtubules from both spindle poles, are generally corrected by the Aurora B error correction pathway. Defects in Aurora B signaling and/or hyperstable kinetochore-microtubules permit incorrect attachments to persist. Shown here is an example of uncorrected merotely, which results in a lagging chromosome. (D) Focusing of supernumerary centrosomes into a pseudo-bipolar spindle can produce merotelic attachments, resulting in lagging chromosomes. (E–F) Defects in establishing and releasing cohesion between sister chromatid pairs can produce chromosome missegregation. (E) Sister chromatid cohesion contributes to a geometric configuration that facilities amphitelic attachment. Premature sister chromatid separation results in random segregation of the sister chromatids. (F) After incomplete resolution of sister chromatids, despite poleward movement of kinetochores, the chromatid arms remain entangled, resulting in a chromosome bridge.

Figure 2. Interphase roles of ‘mitotic’ proteins

Many proteins with known mitotic functions that have been classically considered to function primarily or exclusively during mitosis function during interphase as well. Reported interphase roles of these proteins are depicted here. See text for references.