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Molecular and Cellular Biology, January 2009, p. 68-82, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00581-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Death Receptor-Induced Activation of the Chk2- and Histone H2AX-Associated DNA Damage Response Pathways{triangledown}

Stéphanie Solier, Olivier Sordet, Kurt W. Kohn, and Yves Pommier*

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255

Received 9 April 2008/ Returned for modification 5 June 2008/ Accepted 21 October 2008

TRAIL is an endogenous death receptor ligand also used therapeutically because of its selective proapoptotic activity in cancer cells. In the present study, we examined chromatin alterations induced by TRAIL and show that TRAIL induces a rapid activation of DNA damage response (DDR) pathways with histone H2AX, Chk2, ATM, and DNA-PK phosphorylations. Within 1 h of TRAIL exposure, immunofluorescence confocal microscopy revealed {gamma}-H2AX peripheral nuclear staining ({gamma}-H2AX ring) colocalizing with phosphorylated/activated Chk2, ATM, and DNA-PK inside heterochromatin regions. The marginal distribution of DDR proteins in early apoptotic cells is remarkably different from the focal staining seen after DNA damage. TRAIL-induced DDR was suppressed upon caspase inhibition or Bax inactivation, demonstrating that the DDR activated by TRAIL is downstream from the mitochondrial death pathway. H2AX phosphorylation was dependent on DNA-PK, while Chk2 phosphorylation was dependent on both ATM and DNA-PK. Downregulation of Chk2 decreased TRAIL-induced cell detachment; delayed the activation of caspases 2, 3, 8, and 9; and reduced TRAIL-induced cell killing. Together, our findings suggest that nuclear activation of Chk2 by TRAIL acts as a positive feedback loop involving the mitochondrion-dependent activation of caspases, independently of p53.

* Corresponding author. Mailing address: Bldg. 37, Rm. 5068, NIH, Bethesda, MD 20892-4255. Phone: (301) 496-5944. Fax: (301) 402-0752. E-mail: pommier{at}nih.gov

{triangledown} Published ahead of print on 27 October 2008.

Molecular and Cellular Biology, January 2009, p. 68-82, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00581-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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