Cell cycle arrest at the initiation step of human chromosomal DNA replication causes DNA damage

D. Szüts, Torsten Krude

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Cell cycle arrest in response to environmental effects can lead to DNA breaks. We investigated whether inhibition of DNA replication during the initiation step can lead to DNA damage and characterised a cell-cycle-arrest point at the replication initiation step before the establishment of active replication forks. This arrest can be elicited by the iron chelators mimosine, ciclopirox olamine or 2,2′-bipyridyl, and can be reversed by the removal of the drugs or the addition of excess iron. Iron depletion induces DNA double-strand breaks in treated cells, and activates a DNA damage response that results in focal phosphorylation of histone H2AX, focal accumulation of replication protein A (RPA) and ATR (ATM and Rad3-related kinase), and activation of CHK1 kinase. Abrogation of the checkpoint response does not abolish the cell cycle arrest before the establishment of active DNA replication forks. DNA breaks appear concomitantly with the arrival of cells at the arrest point and persist upon release from the cell cycle block. We conclude that DNA double-strand breaks are the consequence, and not the cause, of cell cycle arrest during the initiation step of DNA replication by iron chelation.

Original languageEnglish
Pages (from-to)4897-4908
Number of pages12
JournalJournal of Cell Science
Volume117
Issue number21
DOIs
Publication statusPublished - Oct 1 2004

Fingerprint

Cell Cycle Checkpoints
DNA Replication
DNA Damage
Iron
DNA Breaks
ciclopirox
Double-Stranded DNA Breaks
Phosphotransferases
Mimosine
Replication Protein A
2,2'-Dipyridyl
Chelating Agents
Histones
Cell Cycle
Phosphorylation
Pharmaceutical Preparations

Keywords

  • DNA damage
  • DNA replication initiation
  • Iron chelator
  • Mimosine

ASJC Scopus subject areas

  • Cell Biology

Cite this

Cell cycle arrest at the initiation step of human chromosomal DNA replication causes DNA damage. / Szüts, D.; Krude, Torsten.

In: Journal of Cell Science, Vol. 117, No. 21, 01.10.2004, p. 4897-4908.

Research output: Contribution to journalArticle

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