Merotelic Kinetochore Orientation Is a Major Mechanism of Aneuploidy in Mitotic Mammalian Tissue Cells

By Daniela Cimini, B. Howell, P. Maddox, A. Khodjakov, F. Degrassi, E. Salmon. Journal of Cell Biology, 2001

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In mitotic cells, an error in chromosome segregation occurs when a chromosome is left near the spindle equator after anaphase onset (lagging chromosome). In PtK1 cells, we found 1.16% of untreated anaphase cells exhibiting lagging chromosomes at the spindle equator, and this percentage was enhanced to 17.55% after a mitotic block with 2 μM nocodazole. A lagging chromosome seen during anaphase in control or nocodazole-treated cells was found by confocal immunofluorescence microscopy to be a single chromatid with its kinetochore attached to kinetochore microtubule bundles extending toward opposite poles. This merotelic orientation was verified by electron microscopy. The single kinetochores of lagging chromosomes in anaphase were stretched laterally (1.2–5.6-fold) in the directions of their kinetochore microtubules, indicating that they were not able to achieve anaphase poleward movement because of pulling forces toward opposite poles. They also had inactivated mitotic spindle checkpoint activities since they did not label with either Mad2 or 3F3/2 antibodies. Thus, for mammalian cultured cells, kinetochore merotelic orientation is a major mechanism of aneuploidy not detected by the mitotic spindle checkpoint. The expanded and curved crescent morphology exhibited by kinetochores during nocodazole treatment may promote the high incidence of kinetochore merotelic orientation that occurs after nocodazole washout.

Subfields: Cell Biology, Molecular Biology, Plant Science

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Citations in the corpus

Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. (2008, background): “Because malorientations are more likely to arise following mitotic delay (Cimini et al., 2001), merotelics are probably present despite the spindle bipolarizing.”
Causes and consequences of aneuploidy in cancer (2012, background): “3 Multiple myeloma 81/385 (21) Melanoma 36/72 (50)”
On the road to cancer: aneuploidy and the mitotic checkpoint (2005, background): “Merotelic attachments, in which one KINETOCHORE is simultaneously attached to microtubules emanating from both poles, might be an important cause of aneuploid”
Boveri revisited: Chromosomal instability, aneuploidy and tumorigenesis (2009, background): “, but if they persist, both sister chromatids might be missegregated towards the same pole or lagging chromosomes might be left in the spindle midzone and excluded from both daughter nucle”
DNA breaks and chromosome pulverization from errors in mitosis (2012, background): “When mitotic cells are released from nocodazole, spindles reassemble abnormally, producing merotelic kinetochore attachments (one kinetochore attached to two opposite spindle poles), lagging chromosomes, and ∼10% of cells with micronucle”
Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation (2001, background): “This reduction appears to be important for preventing errors in chromosome alignment produced by individual kinetochores becoming attached to the ends of microtubules from opposite poles (merotelic attachment) (Cimini et al., 2001), as well as for inactivating the spindle checkpoint signal (Howell e”
Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. (2006, neutral): “aneuploidy in mammalian tissue cells (Cimini et al., 2001).”