Centrosome dynamics as a source of chromosomal instability

Abstract

Accurate segregation of duplicated chromosomes between two daughter cells depends on bi-polar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi-orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics – that is, centrosome disjunction and poleward movement of duplicated centrosomes – as a central target for deregulation of bi-orientation in cancer cells. Here we review novel insights into the mechanisms that underlie centrosome dynamics and discuss how these mechanisms are perturbed in cancer cells to drive chromosome missegregation and advance neoplastic transformation.

Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

“…Cells with impaired centrosome separation are prone to forming asymmetrical spindles that promote merotely and chromosome lagging (26). Consistently, spindle geometry defects were more frequent in Nup88 T and Nup98 +/− Rae1 +/− MEFs than in control MEFs (Figure 7, D-F).…”

“…Incomplete centrosome separation has recently been linked to merotelic attachment, the microtubule-kinetochore attachment defect that yields lagging chromosomes (25). Importantly, PLK1 is part of a signaling cascade that regulates centrosome separation (26). To determine whether centrosome separation is perturbed in Nup88 T and Nup98 +/− Rae1 +/− MEFs, we immunostained MEFs for γ-tubulin and measured the amount of separation between sister centrosomes in the G 2 phase (Figure 7A and ref.…”

“…Sixth, low PLK1 protein levels reproduced the chromosome segregation defects observed in Nup88 T and Nup98 +/-Rae1 +/-MEFs ( Figure 6A), further strengthening the idea that untimely PLK1 degradation is the key abnormality responsible for the CIN phenotype seen in these mutant cell lines. Indeed, reduced PLK1 levels have previously been linked to abnormal centrosome dynamics prior to NEBD as well as reduced separase activity (26,29).…”

“…However, the functions of PLK1 are not limited to mitosis. In fact, PLK1 kinase activity is indispensable for NEK2A-mediated centrosome separation in the late G 2 phase (26,33). Cells with delayed centrosome separation are highly prone to chromosome lagging (25), the most common chromosome segregation error detected in human cancer cells.…”

Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy

“…At mitotic entry, centrosomes move to the opposite ends of the cell, where they act as part of the microtubule organizing center (MTOC). In turn, the MTOC forms the mitotic spindle complex, which ensures proper segregation of sister chromatids and equal partitioning of DNA to daughter cells (reviewed in [4]). Plk1 is the most thoroughly studied member of the Plk family, and its functions are pleiotropic.…”