The Maintenance of ATM Dependent G2/M Checkpoint Arrest Following Exposure to Ionizing Radiation

Atsushi Shibata, Angela T. Noon, Kirsten Dahm, Aaron A. Goodarzi, Penny A. Jeggo, Olivia Barton, Dorothee Deckbar, Markus Löbrich

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The G2/M checkpoint is important in preventing cells with unrepaired DNA double strand breaks (DSBs) entering mitosis, an event which is likely to result in genomic instability. We recently reported that checkpoint arrest is maintained until close to completion of DSB repair and that the duration of checkpoint arrest depends on the dose and DSB repair capacity rather than lasting for a fixed period of time. ATM leads to phosphorylation of Chk1/2 inG2phase following exposure to ionizing radiation. These transducer kinases can phosphorylate and inhibit Cdc25 activity, which is the phosphatase regulating mitotic entry. In this study we dissect three processes that contribute to the maintenance of checkpoint arrest in irradiated G2 phase cells. First, the ATR-Chk1 pathway contributes to maintaining checkpoint arrest, although it is dispensable for the initial activation of checkpoint arrest. Second, ongoing ATM to Chk2 signalling from unrepaired DSBs contributes to checkpoint arrest. This process plays a greater role in a repair defective background. Finally, slow decay of the initially activated Chk2 also contributes to the mantenance of checkpoint arrest. 53BP1 and MDC1 defective cells show an initial checkpoint defect after low doses but are proficient in initial activation of arrest after high doses. After higher radiation doses, however, 53BP1-1- and MDCT-1- MEFs fail to maintain checkpoint arrest. Furthermore 53BP1-1- and MDC1-1- MEFs display elevated mitotic breakage even after high doses. We show thatthe defect in the maintenance of checkpoint arrest conferred by 53BP1 and MDC1 deficiency substantially enhances chromosome breakage.

Original languageEnglish
JournalActa Medica Nagasakiensia
Volume53
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • ATM signalling
  • Cell cycle checkpoints
  • DNA damage response
  • Radiation sensitivity

ASJC Scopus subject areas

  • General Medicine

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