title: Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells.
abstract: Many cancer cells are unable to maintain a numerically stable chromosome complement. It is well established that aberrant cell division can generate progeny with increased ploidy, but the genetic factors required for maintenance of diploidy are not well understood. Using an isogenic model system derived by gene targeting, we examined the role of Chk1 in p53-proficient and -deficient cancer cells. Targeted inactivation of a single CHK1 allele in stably diploid cells caused an elevated frequency of mitotic bypass if p53 was naturally mutated or experimentally disrupted by homologous recombination. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis. These aberrant cell cycles resulted in whole-genome endoreduplication and tetraploidization. The unscheduled bypass of mitosis could be suppressed by targeted reversion of a p53 mutation or by exogenous expression of Cdk1. In contrast, the number of tetraploid cells was not increased in isogenic cell populations that harbor hypomorphic ATR mutations, suggesting that suppression of unscheduled mitotic bypass is a distinct function of Chk1. These results are consistent with a recently described role for Chk1 in promoting the expression of genes that promote cell cycle transitions and demonstrate how Chk1 might prevent tetraploidization during the cancer cell cycle.
authors.affiliation: Molecular Radiation Therapeutics Branch, National Cancer Institute, Frederick, MD, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Wilsker
authors.forename: Jon H
authors.initials: JH
authors.lastname: Chung
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
mesh_terms: D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004171:Diploidy; D045325:HCT116 Cells; D057895:Haploinsufficiency; D059765:Homologous Recombination; D006801:Humans; D008677:Metaphase; D008938:Mitosis; D009154:Mutation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases