The human decatenation checkpoint Academic Article uri icon

Overview

MeSH Major

  • BRCA1 Protein
  • CDC2 Protein Kinase
  • Cell Cycle Proteins
  • Cyclin B
  • Mitosis
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Topoisomerase II Inhibitors

abstract

  • Chromatid catenation is actively monitored in human cells, with progression from G(2) to mitosis being inhibited when chromatids are insufficiently decatenated. Mitotic delay was quantified in normal and checkpoint-deficient human cells during treatment with ICRF-193, a topoisomerase II catalytic inhibitor that prevents chromatid decatenation without producing topoisomerase-associated DNA strand breaks. Ataxia telangiectasia (A-T) cells, defective in DNA damage checkpoints, showed normal mitotic delay when treated with ICRF-193. The mitotic delay in response to ICRF-193 was ablated in human fibroblasts expressing an ataxia telangiectasia mutated- and rad3-related (ATR) kinase-inactive ATR allele (ATR(ki)). BRCA1-mutant HCC1937 cells also displayed a defect in ICRF-193-induced mitotic delay, which was corrected by expression of wild-type BRCA1. Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay. Over-expression of cyclin B1 containing a dominant nuclear localization signal, and inhibition of Crm1-mediated nuclear export, reversed ICRF-193-induced mitotic delay. In combination, these results imply that ATR and BRCA1 enforce the decatenation G(2) checkpoint, which may act to exclude cyclin B1/Cdk1 complexes from the nucleus. Moreover, induction of ATR(ki) produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability.

publication date

  • October 9, 2001

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC59764

Digital Object Identifier (DOI)

  • 10.1073/pnas.221430898

PubMed ID

  • 11593014

Additional Document Info

start page

  • 12044

end page

  • 9

volume

  • 98

number

  • 21