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Nucleic Acids Research 2005 33(16):5320-5330; doi:10.1093/nar/gki821
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Published online 21 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor

Mariana Yaneva1, Han Li2, Teresa Marple2 and Paul Hasty1,2,*

1Lexicon Genetics Inc. The Woodlands, TX 77381-4287, USA 2Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center San Antonio, TX 78245, USA

*To whom correspondence should be addressed. Tel: +1 210 567 7278; Fax: +1 210 567 7247; Email: hastye{at}uthscsa.edu

Received July 21, 2005. Revised August 20, 2005. Accepted August 20, 2005.

Non-homologous end joining (NHEJ) and homologous recombination (HR) are pathways that repair DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, the repair of these breaks is influenced by histone acetylation. Therefore, we tested mammalian cells deleted for NHEJ (Ku80 or DNA Ligase IV) or altered for HR (breast cancer associated gene, Brca2, or Bloom's syndrome, Blm) for sensitivity to trichostatin A (TSA), a histone deacetylase inhibitor that is being investigated as an anti-cancer therapeutic. We show that cells mutated for Ku80 (ku80–/–) or DNA Ligase IV (lig 4–/–), but not cells mutated for Brca2 (brca2lex1/lex2) or Blm (blmtm3Brd/tm4Brd), are hypersensitive to TSA in a dose-dependent manner. TSA-induced toxicity stimulates apoptosis and cell cycle checkpoint responses independent of p53, but does not increase phosphorylated histone H2AX ({gamma}-H2AX) as compared with a clastogenic agent, camptothecin, indicating that the quantity of DSBs is not the primary cause of TSA-induced cell death. In addition, we show that potential anti-cancer drugs (LY-294002 and vanillin) that inhibit the family of phosphatidylinositol 3 kinases that include the NHEJ protein, DNA–PKCS act in synergy with TSA to reduce the viability of HeLa cells in tissue culture presenting the possibility of using the two drugs in combination to treat cancer.

Present address: Mariana Yaneva, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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