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J. Biol. Chem., Vol. 282, Issue 44, 32433-32441, November 2, 2007

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A Triplex-forming Sequence from the Human c-MYC Promoter Interferes with DNA Transcription^*

Boris P. Belotserkovskii, Erandi De Silva, Silvia Tornaletti¹, Guliang Wang, Karen M. Vasquez, and Philip C. Hanawalt²

From the Department of Biological Sciences, Stanford University, Stanford, California 94305 and the Department of Carcinogenesis, University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957

Naturally occurring DNA sequences that are able to form unusual DNA structures have been shown to be mutagenic, and in some cases the mutagenesis induced by these sequences is enhanced by their transcription. It is possible that transcription-coupled DNA repair induced at sites of transcription arrest might be involved in this mutagenesis. Thus, it is of interest to determine whether there are correlations between the mutagenic effects of such noncanonical DNA structures and their ability to arrest transcription. We have studied T7 RNA polymerase transcription through the sequence from the nuclease-sensitive element of the human c-MYC promoter, which is mutagenic in mammalian cells ( Wang, G., and Vasquez, K. M. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 13448-13453[Abstract/Free Full Text] ). This element has two mirror-symmetric homopurine-homopyrimidine blocks that potentially can form either DNA triplex (H-DNA) or quadruplex structures. We detected truncated transcription products indicating partial transcription arrest within and closely downstream of the element. The arrest required negative supercoiling and was much more pronounced when the pyrimidine-rich strand of the element served as the template. The exact positions of arrest sites downstream from the element depended upon the downstream flanking sequences. We made various nucleotide substitutions in the wild-type sequence from the c-MYC nuclease-sensitive element that specifically destabilize either the triplex or the quadruplex structure. When these substitutions were ranked for their effects on transcription, the results implicated the triplex structure in the transcription arrest. We suggest that transcription-induced triplex formation enhances pre-existing weak transcription pause sites within the flanking sequences by creating steric obstacles for the transcription machinery.

Received for publication, June 5, 2007 , and in revised form, July 30, 2007.

^* This work was supported by NCI Grants CA77712 (to P. C. H.) and CA93729 (to K. M. V.) from the National Institutes of Health and by an undergraduate research program grant (to E. de S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Present address: Dept. of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610.

² To whom correspondence should be addressed. Fax: 650-725-1848; E-mail: hanawalt{at}stanford.edu.

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