A model of missegregation

Most human tumors have an abnormal number of chromosomes, implying that something has gone wrong with their mitotic checkpoint systems, but the genes encoding checkpoint proteins are rarely mutated in tumor cells. On page 341, Babu et al. provide a possible explanation for this apparent contradiction and describe new mouse models that should be useful in studying cancer progression.The authors disrupted two highly homologous mouse genes, encoding the nuclear transport factor Rae1 and the checkpoint protein Bub3. Homozygous null mutations in either Rae1 or Bub3 are embryonic lethal. Heterozygous mice with only one copy of Rae1 survive, but exhibit mitotic checkpoint defects and chromosome mis-segregation, and are predisposed to carcinogen-induced lung cancer. Heterozygous Bub3 knockout mice have a strikingly similar phenotype. Surprisingly, overexpressing Rae1 in the mice compensates for haploinsufficiency...