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Nucleic Acids Research 2005 33(17):5382-5393; doi:10.1093/nar/gki851
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Published online 25 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

Triplex targeted genomic crosslinks enter separable deletion and base substitution pathways

Sally Richards, Su-Ting Liu, Alokes Majumdar, Ji-Lan Liu, Rodney S. Nairn1, Michel Bernier2, Veronica Maher3 and Michael M. Seidman*

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health 5600 Nathan Shock Dr, Baltimore, MD 21224, USA 1University of Texas, MD Anderson Cancer Center, Department of Carcinogenesis PO Box 389, 1808 Park Road 1C, Smithville, TX 78957, USA 2Laboratory of Clinical Investigation, NIA/NIH Baltimore, MD 21224, USA 3Carcinogenesis Laboratory, Michigan State University East Lansing, MI 48824, USA

*To whom correspondence should be addressed. Tel: +1 410 558 8565; Fax: +1 410 558 8157; Email: seidmanm{at}grc.nia.nih.gov

Received July 6, 2005. Revised September 3, 2005. Accepted September 3, 2005.

We have synthesized triple helix forming oligonucleotides (TFOs) that target a psoralen (pso) interstrand crosslink to a specific chromosomal site in mammalian cells. Mutagenesis of the targeted crosslinks results in base substitutions and deletions. Identification of the gene products involved in mutation formation is important for developing practical applications of pso-TFOs, and may be informative about the metabolism of other interstrand crosslinks. We have studied mutagenesis of a pso-TFO genomic crosslink in repair proficient and deficient cells. Deficiencies in non homologous end joining and mismatch repair do not influence mutation patterns. In contrast, the frequency of base substitutions is dependent on the activity of ERCC1/XPF and polymerase {zeta}, but independent of other nucleotide excision repair (NER) or transcription coupled repair (TCR) genes. In NER/TCR deficient cells the frequency of deletions rises, indicating that in wild-type cells NER/TCR functions divert pso-TFO crosslinks from processes that result in deletions. We conclude that targeted pso-TFO crosslinks can enter genetically distinct mutational routes that resolve to base substitutions or deletions.


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