The Mad1-Mad2 balancing act--a damaged spindle checkpoint in chromosome instability and cancer

Cancer cells are commonly aneuploid. The spindle checkpoint ensures accurate chromosome segregation by controlling cell cycle progression in response to aberrant microtubule-kinetochore attachment. Damage to the checkpoint, which is a partial loss or gain of checkpoint function, leads to aneuploidy during tumorigenesis. One form of damage is a change in levels of the checkpoint proteins mitotic arrest deficient 1 and 2 (Mad1 and Mad2), or in the Mad1:Mad2 ratio. Changes in Mad1 and Mad2 levels occur in human cancers, where their expression is regulated by the tumor suppressors p53 and retinoblastoma 1 (RB1). By employing a standard assay, namely the addition of a mitotic poison at mitotic entry, it has been shown that checkpoint function is normal in many cancer cells. However, in several experimental systems, it has been observed that this standard assay does not always reveal checkpoint aberrations induced by changes in Mad1 or Mad2, where excess Mad1 relative to Mad2 can lead to premature anaphase entry, and excess Mad2 can lead to a delay in entering anaphase. This Commentary highlights how changes in the levels of Mad1 and Mad2 result in a damaged spindle checkpoint, and explores how these changes cause chromosome instability that can lead to aneuploidy during tumorigenesis.