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Molecular and Cellular Biology, March 2007, p. 1993-2002, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01313-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer ^,

Hisashi Tanaka,^1,2,4* Yi Cao,² Donald A. Bergstrom,^6, Charles Kooperberg,³ Stephen J. Tapscott,² and Meng-Chao Yao^1,5

Divisions of Basic Sciences,¹ Human Biology,² Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, Washington 98109-1024,³ Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, Ohio 44195,⁴ Institute of Molecular Biology, Academia Sinica, 128 Sec. 2 Academia Rd., Nankang, Taipei, Taiwan,⁵ Department of Molecular Medicine, University of Washington, Seattle, Washington⁶

Received 18 July 2006/ Returned for modification 1 November 2006/ Accepted 2 January 2007

Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease. A critical event initiating gene amplification is a DNA double-strand break (DSB), which is immediately followed by the formation of a large DNA palindrome. Large DNA palindromes are frequent and nonrandomly distributed in the genomes of cancer cells and facilitate a further increase in copy number. Although the importance of the formation of large DNA palindromes as a very early event in gene amplification is widely recognized, it is not known how a DSB is resolved to form a large DNA palindrome and whether any local DNA structure determines the location of large DNA palindromes. We show here that intrastrand annealing following a DNA double-strand break leads to the formation of large DNA palindromes and that DNA inverted repeats in the genome determine the efficiency of this event. Furthermore, in human Colo320DM cancer cells, a DNA inverted repeat in the genome marks the border between amplified and nonamplified DNA. Therefore, an early step of gene amplification is a regulated process that is facilitated by DNA inverted repeats in the genome.

Published ahead of print on 22 January 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: MERCK Research Laboratories, West Point, PA 19486-004.