A mechanism linking extra centrosomes to chromosomal instability.

Area of Science:

• Cell Biology
• Cancer Research
• Genetics

Background:

• Chromosomal instability (CIN) is a common feature in many tumours.
• CIN often correlates with the presence of extra centrosomes.
• The mechanistic link between extra centrosomes and CIN has remained unclear.

Purpose of the Study:

• To investigate the mechanistic link between extra centrosomes and chromosomal instability (CIN).
• To determine if extra centrosomes directly cause CIN through multipolar divisions or other mechanisms.
• To elucidate the specific mitotic defects arising from extra centrosomes in cancer cells.

Main Methods:

• Long-term live-cell imaging of cells with varying centrosome numbers.
• Generation of cell lines differing solely in centrosome number.
• Analysis of cell division patterns, including multipolar and bipolar divisions, and chromosome segregation accuracy.

Main Results:

• Cells with extra centrosomes rarely undergo multipolar divisions, and their progeny are often inviable.
• CIN cells with extra centrosomes predominantly exhibit increased chromosome lagging during bipolar divisions.
• Extra centrosomes alone are sufficient to cause chromosome missegregation during bipolar division via a transient multipolar spindle intermediate.

Conclusions:

• Extra centrosomes drive chromosomal instability (CIN) primarily through promoting chromosome missegregation in bipolar divisions, not multipolar ones.
• A transient multipolar spindle intermediate allows merotelic attachment errors, leading to CIN.
• This mechanism provides a direct link between extra centrosomes and CIN, potentially explaining CIN in many human cancers.