Role of ATM and the damage response mediator proteins 53BP1 and MDC1 in the maintenance of G2/M checkpoint arrest

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

Research output: Contribution to journalArticlepeer-review


ATM-dependent initiation of the radiation-induced G2/M checkpoint arrest is well established. Recent results have shown that the majority of DNA double-strand breaks (DSBs) in G2 phase are repaired by DNA nonhomologous end joining (NHEJ), while ∼15% of DSBs are slowly repaired by homologous recombination. Here, we evaluate how the G2/M checkpoint is maintained in irradiated G2 cells, in light of our current understanding of G2 phase DSB repair. We show that ATM-dependent resection at a subset of DSBs leads to ATR-dependent Chk1 activation. ATR-Seckel syndrome cells, which fail to efficiently activate Chk1, and small interfering RNA (siRNA) Chk1-treated cells show premature mitotic entry. Thus, Chk1 significantly contributes to maintaining checkpoint arrest. Second, sustained ATM signaling to Chk2 contributes, particularly when NHEJ is impaired by XLF deficiency. We also show that cells lacking the mediator proteins 53BP1 and MDC1 initially arrest following radiation doses greater than 3 Gy but are subsequently released prematurely. Thus, 53BP1-/- and MDC1-/- cells manifest a checkpoint defect at high doses. This failure to maintain arrest is due to diminished Chk1 activation and a decreased ability to sustain ATM-Chk2 signaling. The combined repair and checkpoint defects conferred by 53BP1 and MDC1 deficiency act synergistically to enhance chromosome breakage.

Original languageEnglish
Pages (from-to)3371-3383
Number of pages13
JournalMolecular and cellular biology
Issue number13
Publication statusPublished - 2010 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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