MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells

The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosi s when chromosomes are unattached to the mitotic spindle(1). The presence o f a single, lagging chromosome is sufficient to activate the checkpoint, pr oducing a delay at the metaphase-anaphase transition until the last spindle attachment is made(2). Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organism s(3-6). Whether partial loss of checkpoint control leads to more subtle rat es of chromosome instability compatible with cell viability remains unknown . Here we report that deletion of one MAD2 allele results in a defective mi totic checkpoint in both human cancer cells and murine primary embryonic fi broblasts. Checkpoint-defective cells show premature sister-chromatid separ ation in the presence of spindle inhibitors and an elevated rate of chromos ome mis-segregation events in the absence of these agents. Furthermore, Mad 2(+/-) mice develop lung tumours at high rates after long latencies, implic ating defects in the mitotic checkpoint in tumorigenesis.