DNA secondary structure: A common and causative factor for expansion in human disease

McMurray, Cynthia T.

doi:10.1073/pnas.96.5.1823

Cited by 209 publications

(152 citation statements)

References 42 publications

(62 reference statements)

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“…ODNs targeting the lagging-strand template efficiently released replication fork stalling, suggesting that formation of hairpins during replication is coordinated between the two template strands. Hairpin-forming sequences have also been shown to trigger TNR instability (2,28,29). Strikingly, ODN treatment that eliminated hairpin formation and replication fork stalling also ameliorated TNR instability.…”

mentioning

confidence: 95%

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Liu

Chen

Leffak

2013

Molecular and Cellular Biology

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(CTG) n · (CAG) n trinucleotide repeat (TNR) expansion in the 3= untranslated region of the dystrophia myotonica protein kinase (DMPK) gene causes myotonic dystrophy type 1. However, a direct link between TNR instability, the formation of noncanonical (CTG) n · (CAG) n structures, and replication stress has not been demonstrated. In a human cell model, we found that (CTG) 45 · (CAG) 45 causes local replication fork stalling, DNA hairpin formation, and TNR instability. Oligodeoxynucleotides (ODNs) complementary to the (CTG) 45 · (CAG) 45 lagging-strand template eliminated DNA hairpin formation on leading-and laggingstrand templates and relieved fork stalling. Prolonged cell culture, emetine inhibition of lagging-strand synthesis, or slowing of DNA synthesis by low-dose aphidicolin induced (CTG) 45 · (CAG) 45 expansions and contractions. ODNs targeting the laggingstrand template blocked the time-dependent or emetine-induced instability but did not eliminate aphidicolin-induced instability. These results show directly that TNR replication stalling, replication stress, hairpin formation, and instability are mechanistically linked in vivo.

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mentioning

confidence: 95%

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Liu

Chen

Leffak

2013

Molecular and Cellular Biology

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“…(Gordenin et al, 1997). Structural studies of TNR DNA point out that single strand (ss) -triplet repeat DNA (CNG, N equals the nucleotides, A, G, C, or T) can partially form hairpin structures, as demonstrated by NMR and biochemical studies (Mitas, 1997;McMurray, 1999). During lagging strand synthesis, which has a greater chance to form ss regions compared to leading strand synthesis, the unusual structural formation (hairpintype) from ss DNA can give rise to replication errors at the TNR loci.…”

Section: Introductionmentioning

confidence: 99%

Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner

Lee

Park²

2002

Exp Mol Med

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Trinucleotide repeat (TNR) instability can cause a variety of human genetic diseases including myotonic dystrophy and Huntington's disease. Recent genetic data show that instability of the CAG/CTG repeat DNA is dependent on its length and replication origin. In yeast, the RAD27 (human FEN-1 homologue) null mutant has a high expansion frequency at the TNR loci. We demonstrate here that FEN-1 processes the 5'-flap DNA of CTG/CAG repeats, which is dependent on the length in vitro. FEN-1 protein can cleave the 5'-flap DNA containing triplet repeating sequence up to 21 repeats, but the activity decreases with increasing size of flap above 11 repeats. In addition, FEN-1 processing of 5'-flap DNA depends on sequence, which play a role in the replication origin-dependent TNR instability. Interestingly, FEN-1 can cleave the 5'-flap DNA of CTG repeats better than CAG repeats possibly through the flap-structure. Our biochemical data of FEN-1's activity with triplet repeat DNA clearly shows length dependence, and aids our understanding on the mechanism of TNR instability.

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“…The repetitive and G/C-rich nature of the sequences surrounding the close and partly overlapping duplications of the FEO, early-onset PDB, and ESH duplications are likely to promote mutation events [15]. The preponderance of CTG repeats may be particularly important in this regard [16]. …”

Section: Discussionmentioning

confidence: 99%

Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation

et al. 2007

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. (2007). Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation. Journal of Bone and Mineral Metabolism, 25(3) Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation Abstract Familial expansile osteolysis (FEO) is a rare disorder causing bone dysplasia. The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity. An 18-bp duplication in the fi rst exon of the TNFRSF11A gene encoding RANK has been previously identifi ed in four FEO pedigrees. Despite having the identical mutation, phenotypic variations among affected individuals of the same and different pedigrees were noted. Another 18-bp duplication, one base proximal to the duplication previously reported, was subsequently found in two unrelated FEO patients. Finally, mutations overlapping with the mutations found in the FEO pedigrees have been found in ESH and early-onset PDB pedigrees. An Iranian FEO pedigree that contains six affected individuals dispersed in three generations has previously been introduced; here, the clinical features of the proband are reported in greater detail, and the genetic defect of the pedigree is presented. Direct sequencing of the entire coding region and upstream and downstream noncoding regions of TNFRSF11A in her DNA revealed the same 18-bp duplication mutation as previously found in the four FEO pedigrees. Additionally, eight sequence variations as compared to the TNFRSF11A reference sequence were identifi ed, and a haplotype linked to the mutation based on these variations was defi ned. Although the mutation in the Iranian and four of the previously described FEO pedigrees was the same, haplotypes based on the intragenic SNPs suggest that the mutations do not share a common descent.

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DNA secondary structure: A common and causative factor for expansion in human disease

Cited by 209 publications

References 42 publications

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner

Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation

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