The pattern of gene amplification is determined by the chromosomal location of hairpin-capped breaks.
DNA palindromes often colocalize in cancer cells with chromosomal regions that are predisposed to gene amplification. The molecular mechanisms by which palindromes can cause gene amplification are largely unknown. Using yeast as a model system, we found that hairpin-capped double-strand breaks (DSBs) occurring at the location of human Alu-quasipalindromes lead to the formation of intrachromosomal amplicons with large inverted repeats (equivalent to homogeneously staining regions in mammalian chromosomes) or extrachromosomal palindromic molecules (equivalent to double minutes [DM] in mammalian cells). We demonstrate that the specific outcomes of gene amplification depend on the applied selection, the nature of the break, and the chromosomal location of the amplified gene relative to the site of the hairpin-capped DSB. The rules for the palindrome-dependent pathway of gene amplification defined in yeast may operate during the formation of amplicons in human tumors.
Narayanan
Vidhya
V
School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Mieczkowski
Piotr A
PA
Kim
Hyun-Min
HM
Petes
Thomas D
TD
Lobachev
Kirill S
KS
D020087:Alu Elements; D019457:Chromosome Breakage / Q000235:genetics*; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics; D009690:Nucleic Acid Conformation; D012091:Repetitive Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000235:genetics
D004271:DNA, Fungal; D004273:DNA, Neoplasm; D004247:DNA