DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response

Rachel A. Freiberg, Ester M. Hammond, Mary Jo Dorie, Scott Welford, Amato J. Giaccia

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Due to the abnormal vasculature of solid tumors, tumor cell oxygenation can change rapidly with the opening and closing of blood vessels, leading to the activation of both hypoxic response pathways and oxidative stress pathways upon reoxygenation. Here, we report that ataxia telangiectasia mutated-dependent phosphorylation and activation of Chk2 occur in the absence of DNA damage during hypoxia and are maintained during reoxygenation in response to DNA damage. Our studies involving oxidative damage show that Chk2 is required for G2 arrest. Following exposure to both hypoxia and reoxygenation, Chk2-/- cells exhibit an attenuated G2 arrest, increased apoptosis, reduced clonogenic survival, and deficient phosphorylation of downstream targets. These studies indicate that the combination of hypoxia and reoxygenation results in a G2 checkpoint response that is dependent on the tumor suppressor Chk2 and that this checkpoint response is essential for tumor cell adaptation to changes that result from the cycling nature of hypoxia and reoxygenation found in solid tumors.

Original languageEnglish (US)
Pages (from-to)1598-1609
Number of pages12
JournalMolecular and Cellular Biology
Volume26
Issue number5
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

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DNA Damage
Neoplasms
Phosphorylation
Ataxia Telangiectasia
Blood Vessels
Oxidative Stress
Apoptosis
Hypoxia

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. / Freiberg, Rachel A.; Hammond, Ester M.; Dorie, Mary Jo; Welford, Scott; Giaccia, Amato J.

In: Molecular and Cellular Biology, Vol. 26, No. 5, 01.03.2006, p. 1598-1609.

Research output: Contribution to journalArticle

Freiberg, Rachel A. ; Hammond, Ester M. ; Dorie, Mary Jo ; Welford, Scott ; Giaccia, Amato J. / DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 5. pp. 1598-1609.
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