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J. Biol. Chem., Vol. 279, Issue 34, 35377-35383, August 20, 2004

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Cruciform DNA Structure Underlies the Etiology for Palindrome-mediated Human Chromosomal Translocations^*

Hiroki Kurahashi¶, Hidehito Inagaki, Kouji Yamada, Tamae Ohye, Mariko Taniguchi, Beverly S. Emanuel||**, and Tatsushi Toda

From the Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan, the Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, the ^||Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, and the ^**Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

There is accumulating evidence to suggest that palindromic AT-rich repeats (PATRRs) represent hot spots of double-strand breakage that lead to recurrent chromosomal translocations in humans. As a mechanism for such rearrangements, we proposed that the PATRR forms a cruciform structure that is the source of genomic instability. To test this hypothesis, we have investigated the tertiary structure of a cloned PATRR. We have observed that a plasmid containing this PATRR undergoes a conformational change, causing temperature-dependent mobility changes upon agarose gel electrophoresis. The mobility shift is observed in physiologic salt concentrations and is most prominent when the plasmid DNA is incubated at room temperature prior to electrophoresis. Analysis using two-dimensional gel electrophoresis indicates that the mobility shift results from the formation of a cruciform structure. S1 nuclease and T7 endonuclease both cut the plasmid into a linear form, also suggesting cruciform formation. Furthermore, anti-cruciform DNA antibody reduces the electrophoretic mobility of the PATRR-containing fragment. Finally, we have directly visualized cruciform extrusions from the plasmid DNA with the size expected of hairpin arms using atomic force microscopy. Our data imply that for human chromosomes, translocation susceptibility is mediated by PATRRs and likely results from their unstable conformation.

Received for publication, January 13, 2004 , and in revised form, June 10, 2004.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan (to H. K.) and Grants HD26079 and CA39926 from the Charles E. H. Upham chair in Pediatrics (to B. S. E.). 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.

^¶ To whom correspondence should be addressed: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. Tel.: 81-562-93-9391; Fax: 81-562-93-8831; E-mail: kura{at}fujita-hu.ac.jp.

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