Structure of a palindromic amplicon junction implicates microhomology-mediated end joining as a mechanism of sister chromatid fusion during gene amplification

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Abstract
Amplification of the copy number of oncogenes is frequently associated with tumor progression. Often, the amplified DNA consists of large (tens to hundreds of kilobases) 'head-to-head' inverted repeat palindromes (amplicons). Several mechanisms have been proposed to explain palindrome formation but their relative contributions in nature have been difficult to assess without precise knowledge of the sequences involved at the junction of natural amplicons. Here, we have sequenced one such junction and compared this sequence to the un-rearranged structure, allowing us to pinpoint the site of sister chromatid fusion. Our results support a novel model, consistent with all described sister chromatid fusions, in which sister chromatid fusion is initiated by microhomology-mediated end joining of double strand breaks.