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Sci. Signal., 1 June 2010
Vol. 3, Issue 124, p. ra44
[DOI: 10.1126/scisignal.2000758]


Transient ATM Kinase Inhibition Disrupts DNA Damage–Induced Sister Chromatid Exchange

Jason S. White1*, Serah Choi2, and Christopher J. Bakkenist1,3{dagger}

1 Department of Radiation Oncology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213–1863, USA.
2 Medical Scientist Training Program, Molecular Pharmacology Graduate Program, University of Pittsburgh Medical School, Pittsburgh, PA 15213–1863, USA.
3 Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Hillman Cancer Center, Pittsburgh, PA 15213–1863, USA.

* Present address: BioCytics, Inc, 9801 W Kincey Avenue, Suite 145, Huntersville, NC 28078, USA.

Abstract: Cells derived from ataxia telangiectasia (A-T) patients exhibit defective cell cycle checkpoints because of mutations in the gene encoding ATM (ataxia telangiectasia mutated). After exposure to ionizing radiation (IR), A-T cells exhibit sensitivity to IR-induced cellular damage that results in increased chromosome aberrations and cell death (radiosensitivity). ATM is a member of a family of kinases that become activated in response to DNA damage. We showed that even transient inhibition of ATM kinase for 1 hour, initiated 15 minutes after cellular irradiation, resulted in an accumulation of persistent chromosome aberrations and increased cell death. Using reversible inhibitors of DNA-PK (DNA-dependent protein kinase), another kinase involved in responding to DNA damage, and ATM, we showed that these two kinases acted through distinct DNA repair mechanisms: ATM resolved DNA damage through a mechanism involving sister chromatid exchange (SCE), whereas DNA-PK acted through nonhomologous end joining. Furthermore, because DNA damage–induced SCE occurred in A-T fibroblasts that lack functional ATM protein, and the inhibitors of ATM kinase had no effect on DNA damage–induced SCE in A-T fibroblasts, we showed that the consequences of short-term inhibition of the kinase activity of ATM and adaptation to ATM protein disruption were distinct. This suggests that A-T fibroblasts have adapted to the loss of ATM and have alternative mechanisms to initiate SCE.

{dagger} To whom correspondence should be addressed. E-mail: bakkenistcj{at}

Citation: J. S. White, S. Choi, C. J. Bakkenist, Transient ATM Kinase Inhibition Disrupts DNA Damage–Induced Sister Chromatid Exchange. Sci. Signal. 3, ra44 (2010).

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