Inverted DNA repeats: a source of eukaryotic genomic instability.

Gordenin, Dmitry A.; Lobachev, Kirill S.; Degtyareva, Natasha P.; Malkova, A L; Perkins, E; Resnick, Michael A.

doi:10.1128/mcb.13.9.5315

Cited by 142 publications

(148 citation statements)

References 16 publications

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“…The present study considerably extends our recent report demonstrating a reduction in closely spaced inverted Alus as compared to direct Alu repeats (Lobachev et al 2000). Based on results from model systems, other factors also are likely to be important in the stability of Alu sites including genetic background (Gordenin et al 1993;Ruskin and Fink 1993;Tran et al 1997;Lobachev et al 1998Lobachev et al , 2000). For example, recombination in mammalian cell constructs containing direct identical Alu repeats is high in p53 defective as compared to p53 wildtype cells (Gebow et al 2000).…”

Section: Discussion General Approach To Investigating Alu Distributionsupporting

confidence: 66%

“…Pairs of large inverted DNA repeats can be unstable, lead to deletions, and stimulate recombination between DNAs surrounding the inverted repeats in yeast (Gordenin et al 1993;Ruskin and Fink 1993;Nag and Kurst 1997;Tran et al 1997;Lobachev et al 1998Lobachev et al , 2000 ) and mammalian cells (Akgun et al 1997;Lewis 1999;Lewis et al 1999). Sequence identity was suggested as a likely factor in the stability of Alu repeats based on results in yeast.…”

Section: Discussion General Approach To Investigating Alu Distributionmentioning

confidence: 99%

“…Observations with yeast and mouse cells suggest that long closely related inverted repeats are unstable and can cause deletions in eukaryotes (Gordenin et al 1993;Ruskin and Fink 1993;Lewis 1999;Lewis et al 1999). Moreover, they are initiators of recombination in yeast (Gordenin et al 1993;Nag and Kurst 1997;Lobachev et al 1998). This has led us to propose that long inverted repeats can be at-risk motifs (ARMs) in the genome .…”

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confidence: 99%

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Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Stenger

Lobachev²,

Gordenin³

et al. 2001

Genome Res.

117

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Alu sequences, the most abundant class of large dispersed DNA repeats in human chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential for interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an extensive computational analysis of all Alus (the database is at http://dir.niehs.nih.gov/ALU) to better understand their distribution and circumstances under which Alu sequences might affect genome stability. Alus separated by <650 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and extent of sequence identity. Nearly 50% of all Alu pairs have long alignable regions (>275 bp), corresponding to nearly full-length Alus, regardless of orientation. There are dramatic differences in the distributions and character of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, ∼30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full-size or half-size Alus. The opposite is found for the distribution of inverted repeats: Alu pairs with aligned regions separated by <20 bp are rare. Furthermore, closely spaced direct and inverted Alus differ in their truncation patterns, suggesting differences in the mechanisms of insertion. At larger distances, the direct and inverted Alu pairs have similar distributions. We propose that sequence identity, orientation, and distance are important factors determining insertion of adjacent Alus, the frequency and spectrum of Alu-associated changes in the genome, and the contribution of Alu pairs to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs) for genome instability.

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Section: Discussion General Approach To Investigating Alu Distributionsupporting

confidence: 66%

Section: Discussion General Approach To Investigating Alu Distributionmentioning

confidence: 99%

mentioning

confidence: 99%

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Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Stenger

Lobachev²,

Gordenin³

et al. 2001

Genome Res.

117

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“…Palindromic repetitive sequences remain as a subset of these gaps because of difficulties in PCR amplification, cloning, and sequencing. Frequent deletions prevent cloning in E. coli or yeast [Leach, 1994;Gordenin et al, 1993], while PCR or sequencing is also difficult because of the secondary structures adopted by the template DNA.…”

Section: Introductionmentioning

confidence: 99%

Palindromic AT-rich repeat in theNF1gene is hypervariable in humans and evolutionarily conserved in primates

et al. 2005

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Palindromic sequences are dispersed in the human genome and may cause chromosomal translocations in humans. They constitute unsequenced gaps in the human genome because of their resistance to PCR amplification, cloning into vectors, and sequencing. We have overcome these difficulties by using a combination of optimized PCR conditions, cloning in a recombinationdeficient E. coli strain, and RNA polymerases in sequencing. Using these methods, we analyzed a palindromic AT-rich repeat (PATRR) in the neurofibromatosis type 1 (NF1) gene on chromosome 17 (17PATRR). The 17PATRR manifests a size polymorphism due to a highly variable length of (AT) n dinucleotide repeats within the PATRR. 17PATRRs can be categorized into two types: a longer one that comprises a nearly or completely perfect palindrome, and a shorter one that represents its deleted asymmetric derivative. In vitro analysis shows that the longer 17PATRR is more likely to form a cruciform structure than the shorter one. Two reported t(17;22)(q11;q11) patients with NF1, whose breakpoints were identified within the 17PATRR, have translocations that are derived from perfect or nearly perfect palindromic alleles. This implies that the symmetric structure of a PATRR can induce a translocation. We identified conserved PATRRs within the NF1 gene in great apes and similar inverted repeats in two Old World monkeys, but not in New World monkeys or other mammals. This indicates that the palindromic region appeared approximately 25 million years ago and elongated during primate evolution. Although such palindromic regions are usually unstable and disappear rapidly due to deletion, the 17PATRR in the NF1 gene was stably conserved during evolution for reasons that are still unknown.

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“…Often, a donor repeat is present within the palindrome and a target repeat is located outside (Trinh and Sinden, 1991;Weston-Hafer and Berg, 1991;Leach, 1994;Rosche et al, 1995). Palindromic DNA is also unstable in the genomes of Bacillus (Peeters et al, 1988), Streptococcus (Behnke et al, 1979), Streptomyces (Kieser and Melton, 1988), Saccharomyces cerevisiae (Gordenin et al, 1993;Henderson and Petes, 1993;Ruskin and Fink, 1993) mouse (Collick et al, 1996;Akgun et al, 1997) and humans (Kramer et al, 1996, and references therein).…”

Section: Introductionmentioning

confidence: 99%

Repair by recombination of DNA containing a palindromic sequence

Leach

Okely

Pinder

1997

Molecular Microbiology

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SummaryWe report here that homologous recombination functions are required for the viability of Escherichia coli cells maintaining a 240 bp chromosomal inverted repeat (palindromic) sequence. Wild-type cells can successfully replicate this palindrome but recA, recB or recC mutants carrying the palindrome are unviable. The dependence on homologous recombination for cell viability is overcome in sbcC mutants. Directly repeated copies of the DNA containing the palindrome are rapidly resolved to single copies in wild-type cells but not in sbcC mutants. Our results suggest that double-strand breaks introduced at the palindromic DNA sequence by the SbcCD nuclease are repaired by homologous recombination. The repair is conservative and the palindrome is retained in the repaired chromosome. We conclude that SbcCD can attack secondary structures but that repair conserves the DNA sequence with the potential to fold.

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Inverted DNA repeats: a source of eukaryotic genomic instability.

Cited by 142 publications

References 16 publications

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Palindromic AT-rich repeat in theNF1gene is hypervariable in humans and evolutionarily conserved in primates

Repair by recombination of DNA containing a palindromic sequence

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