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Bendre S , Hall C, Rondelet A, Wöstehoff N., Lin Y-C, Brouhard GJ, and Bird AW (2016). GTSE1 tunes microtubule dynamics for chromosome alignment and segregation through MCAK inhibition. J Cell Biol 215(5):631-647.
On the Cover
Missegregation of DNA during the cell division can lead to chromosomal instability (CIN), a characteristic of most human cancers. The Bird lab revealed a so far unknown mechanism that determines the fidelity of chromosome stability.
January 25, 2017
During cell division, paired copies of chromosomes are aligned by a microtubule network termed the mitotic spindle, followed by their separation and segregation into the newly forming daughter cells. A critical, error-prone step in this process is the attachment of the spindle microtubules to the chromosomes via the kinetochores, protein structures anchored on the chromosomes. This process turns out to be a balancing act: kinetochore microtubules must be stable enough to capture and align chromosomes, but at the same time loose enough to quickly allow corrections of incorrect attachments. Cancer cells often have hyperstable kinetochore microtubules that lead to an inability to correct erroneous attachments, resulting in chromosome missegregation. Repeated missegregation of chromosomes leads to a cell population with a constantly changing number of chromosomes, a phenomenon termed “chromosomal instability” or CIN.
Chromosomal instability is the main cause of tumour aneuploidy and genetic heterogeneity of cancer cells. Tumours thereby better adapt to their environment and resist pressure coming from drug treatment. CIN is therefore associated with drug resistance and poor patient outcome. Hence, it is essential to understand how CIN is induced and which molecular players and mechanisms are involved.
GTSE1 regulates the right balance of kinetochore microtubule stability
In the Journal of Cell Biology, Alex Bird and his colleagues revealed that the microtubule-associated protein GTSE1 can influence CIN by regulating the right balance of kinetochore microtubule stability. The scientists showed that GTSE1 promotes microtubule stability by inhibiting the activity of a potent microtubule-destabilizing enzyme in the cell. Interestingly, GTSE1 is inappropriately highly expressed in several different tumour types, and its expression correlates with tumour grade and poor clinical outcome in breast cancers1. Consistent with the idea that excessively high levels of GTSE1 hyperstabilize microtubules and therefore induce CIN, Bird and colleagues showed that reducing GTSE1 amounts in overexpressing cancer cell lines reduced chromosome missegregation significantly, whereas artificially inducing GTSE1 levels in stable cell lines increased chromosome missegregation and CIN. Elucidating mechanistic insights into the causes of CIN will help to design potential therapies targeting CIN in cancers.
Literature:1) Scolz M, Widlund PO, Piazza S, Bublik DR, Reber S, Peche LY, Ciani Y, Hubner N, Isokane M, Monte M, Ellenberg J, Hyman AA, Schneider C, Bird AW (2012). GTSE1 is a microtubule plus-end tracking protein that regulates EB1-dependent cell migration. PLoS One e51259.