Intrastrand annealing leads to the formation of a large DNA palindrome and determines the boundaries of genomic amplification in human cancer.
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.
Tanaka
Hisashi
H
Fred Hutchinson Cancer Reserach Center, Seattle, WA 98109, USA. tanakah@ccf.org
Cao
Yi
Y
Bergstrom
Donald A
DA
Kooperberg
Charles
C
Tapscott
Stephen J
SJ
Yao
Meng-Chao
MC
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*
D004247:DNA; D008727:Methotrexate