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

Loren S. Michel, Vasco Liberal, Anupam Chatterjee, Regina Kirchwegger, Boris Pasche, William Gerald, Max Dobles, Peter K. Sorger, V. V. V. S. Murty and Robert Benezra ()
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Loren S. Michel: and
Vasco Liberal: Graduate School of Medical Sciences, Cornell University
Anupam Chatterjee: College of Physicians and Surgeons of Columbia University
Regina Kirchwegger: Graduate School of Medical Sciences, Cornell University
Boris Pasche: Northwestern University Medical School
William Gerald: Memorial Sloan-Kettering Cancer Center
Max Dobles: Massachusetts Institute of Technology
Peter K. Sorger: Massachusetts Institute of Technology
V. V. V. S. Murty: College of Physicians and Surgeons of Columbia University
Robert Benezra: Graduate School of Medical Sciences, Cornell University

Nature, 2001, vol. 409, issue 6818, 355-359

Abstract: Abstract The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle1. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase–anaphase transition until the last spindle attachment is made2. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms3,4,5,6. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

Date: 2001
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DOI: 10.1038/35053094

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