A Mechanism Linking Extra Centrosomes to Chromosomal Instability

By Neil J. Ganem, S. Godinho, D. Pellman. Nature, 2009

1,451 citations recorded by the source corpus.

Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient ‘multipolar spindle intermediate’ in which merotelic kinetochore–microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.

Subfields: Cancer Research, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f7faa590bc5ed4d9b31e3c0b3159d67c1cfc12d1

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Citations in the corpus

Absolute quantification of somatic DNA alterations in human cancer (2012, background): “…in genome-doubled samples may reflect the fact that more events are required to render a mutation homozygous in a genome-doubled sample (although the effect may be partially offset, however, by a possible increase in genetic instability following doubling, e.g., by centrosome duplication 42 ).”
Cell mechanics and the cytoskeleton (2010, neutral): “Chromosomal instability is associated either with a loss of the checkpoint that ensures that all chromosomes are correctly attached to microtubules in the mitotic spindle or with the presence of too many microtubule-organizing centres at the time of cell divisio”
Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease (2010, background): “As genomic instability has been linked to centrosomal aberration”
DNA breaks and chromosome pulverization from errors in mitosis (2012, neutral): “Whole-chromosome-containing micronuclei form from anaphase lagging chromosome”
Centrioles, centrosomes, and cilia in health and disease. (2009, background): “Recent studies, however, reveal that centrosome amplification can lead to an increase in chromosome missegregation even when the centrosomes cluster, due to increased rates of merotelic chromosomal attachments to the spindle (where a single sister kinetochore becomes simultaneously attached to two s”
Boveri revisited: Chromosomal instability, aneuploidy and tumorigenesis (2009, background): “Time-lapse imaging has revealed that the progeny of multipolar divisions are typically inviabl”