title: Inverted Alu repeats unstable in yeast are excluded from the human genome.
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.
authors.affiliation: Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Lobachev
authors.forename: J E
authors.initials: JE
authors.lastname: Stenger
authors.forename: O G
authors.initials: OG
authors.lastname: Kozyreva
authors.forename: J
authors.initials: J
authors.lastname: Jurka
authors.forename: D A
authors.initials: DA
authors.lastname: Gordenin
authors.forename: M A
authors.initials: MA
authors.lastname: Resnick
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D019295:Computational Biology; D004258:DNA Polymerase III; D004271:DNA, Fungal / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D045585:Flap Endonucleases; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005800:Genes, Fungal / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D009154:Mutation / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D015003:Yeasts / Q000235:genetics*
chemical_list: D004271:DNA, Fungal; D005656:Fungal Proteins; D005819:Genetic Markers; C103317:MET18 protein, S cerevisiae; C491232:POL3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004258:DNA Polymerase III; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human