Inverted Alu repeats unstable in yeast are excluded from the human genome |
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Authors: | Lobachev K S Stenger J E Kozyreva O G Jurka J Gordenin D A Resnick M A |
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Institution: | Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. |
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Abstract: | The nearly one million ALU: repeats in human chromosomes are a potential threat to genome integrity. ALU:s form dense clusters where they frequently appear as inverted repeats, a sequence motif known to cause DNA rearrangements in model organisms. Using a yeast recombination system, we found that inverted ALU: pairs can be strong initiators of genetic instability. The highly recombinagenic potential of inverted ALU: pairs was dependent on the distance between the repeats and the level of sequence divergence. Even inverted ALU:s that were 86% homologous could efficiently stimulate recombination when separated by <20 bp. This stimulation was independent of mismatch repair. Mutations in the DNA metabolic genes RAD27 (FEN1), POL3 (polymerase delta) and MMS19 destabilized widely separated and diverged inverted ALU:s. Having defined factors affecting inverted ALU: repeat stability in yeast, we analyzed the distribution of ALU: pairs in the human genome. Closely spaced, highly homologous inverted ALU:s are rare, suggesting that they are unstable in humans. ALU: pairs were identified that are potential sites of genetic change. |
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