Abstract
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.
Highlights
IntroductionAmplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease
Amplification of large chromosomal regions is a common somatic alteration in human cancer cells and often is associated with advanced disease
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
Summary
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. 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. In Tetrahymena, amplification of the rRNA (rDNA) gene is initiated by the formation of large palindromic chromosomes with the developmentally regulated induction of a site-specific DSB next to a short DNA inverted repeat (DNA IR) in the genome [42]. DSBs initiate intramolecular recombination (intrastrand annealing) at the site of the short DNA IR, creating a large hairpin molecule prior to DNA replication This hairpin molecule is resolved into a large palindrome following DNA replication, with the original DNA IR at a boundary between amplified and nonamplified DNA [6, 43]. A DNA IR in the genome is a critical cis-acting element for the formation of large palin-
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