Impact of G₂ checkpoint defect on centromeric instability.
Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G(2) checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G(2) to M phase transition, impaired G(2) checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G(2) checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G(2) checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G(2) checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G(2) checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G(2) checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.
Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
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W
Deng
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Tsao
G W Y
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Mak
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Tsang
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Ching
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Guan
M S Y
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Huen
A L M
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Cheung
D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002503:Centromere / Q000187:drug effects / Q000378:metabolism*; D043171:Chromosomal Instability / Q000235:genetics*; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology; D016195:G2 Phase / Q000235:genetics*; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008940:Mitotic Index; D009025:Morpholines / Q000494:pharmacology; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011753:Pyrones / Q000494:pharmacology; D019098:Telomerase / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D004268:DNA-Binding Proteins; D009025:Morpholines; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase