Impact of G₂ checkpoint defect on centromeric instability.

Abstract:

: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.

journal_name

Oncogene

journal_title

Oncogene

authors

Deng W,Tsao SW,Mak GW,Tsang CM,Ching YP,Guan XY,Huen MS,Cheung AL

doi

10.1038/onc.2010.508

subject

Has Abstract

pub_date

2011-03-17 00:00:00

pages

1281-9

issue

11

eissn

0950-9232

issn

1476-5594

pii

onc2010508

journal_volume

30

pub_type

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