Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability

Bill Chang, L. Smith, J. Huang, Mathew (Matt) Thayer

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Certain chromosome rearrangements display a significant delay in chromosome replication timing (DRT) that is associated with a subsequent delay in mitotic chromosome condensation (DMC). DRT/DMC chromosomes are common in tumor cells in vitro and in vivo and occur frequently in cells exposed to ionizing radiation. A hallmark for these chromosomes is the delayed phosphorylation of serine 10 of histone H3 during mitosis. The chromosome passenger complex, consisting of multiple proteins including Aurora B kinase and INCENP is thought to be responsible for H3 phosphorylation, chromosome condensation and the subsequent segregation of chromosomes. In this report, we show that chromosomes with DRT/DMC contain phosphorylated Chk1, consistent with activation of the S-M phase checkpoint. Furthermore, we show that INCENP is recruited to the DRT/DMC chromosomes during all phases of mitosis. In contrast, Aurora B kinase is absent on DRT/DMC chromosomes when these chromosomes lack serine 10 phosphorylation of H3. We also show that mitotic arrest deficient 2 (Mad2), a member of the spindle assembly checkpoint, is present on DRT/DMC chromosomes at a time when the normally condensed chromosomes show no Mad2 staining, indicating that DRT/DMC activates the spindle assembly checkpoint. Finally, cells with DRT/DMC chromosomes have centrosome amplification, abnormal spindle assembly, endoreduplication and significant chromosome instability.

Original languageEnglish (US)
Pages (from-to)1852-1861
Number of pages10
JournalOncogene
Volume26
Issue number13
DOIs
StatePublished - Mar 22 2007

Fingerprint

Chromosomal Instability
Chromosomes
DNA Replication Timing
M Phase Cell Cycle Checkpoints
Aurora Kinase B
Phosphorylation
Mitosis
Serine
S Phase Cell Cycle Checkpoints
Endoreduplication
Centrosome

Keywords

  • Chromosome instability
  • Chromosome passenger complex
  • Endoreduplication
  • Genomic instability
  • Replication checkpoint
  • Spindle assembly checkpoint

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. / Chang, Bill; Smith, L.; Huang, J.; Thayer, Mathew (Matt).

In: Oncogene, Vol. 26, No. 13, 22.03.2007, p. 1852-1861.

Research output: Contribution to journalArticle

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