Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases.

Jaworski, Adam; Rosche, William A.; Gellibolian, Robert; Kang, Seongman; Shimizu, Miho; Bowater, Richard P.; Sinden, Richard R.; Wells, Robert D.

doi:10.1073/pnas.92.24.11019

Cited by 144 publications

(145 citation statements)

References 23 publications

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“…For example, mismatch repair was found to be involved in CAG and CGG repeat instability E. coli (42). We and others have shown that intermolecular triplexes are recognized by the nucleotide excision repair (NER) factors XPA and RPA, followed by an error-prone repair resulting in site-specific mutagenesis, both in cells and in animals (19,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells

Wang

Vásquez

2004

Proc. Natl. Acad. Sci. U.S.A.

176

179

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Naturally occurring DNA sequences can form noncanonical structures such as H-DNA, which are abundant and regulate the expression of several disease-linked genes. Here, we show that H-DNAforming sequences are intrinsically mutagenic in mammalian cells. This finding suggests that DNA is a causative factor in mutagenesis and not just the end product. By using the endogenous H-DNAforming sequence found in the human c-myc promoter, mutation frequencies in a reporter gene were increased Ϸ20-fold over background in COS-7 cells. H-DNA-induced double-strand breaks (DSBs) were detected near the H-DNA locus. The structures of the mutants revealed microhomologies at the breakpoints, consistent with a nonhomologous end-joining repair of the DSBs. These results implicate H-DNA-induced DSBs in c-myc gene translocations in diseases such as Burkitt's lymphoma and t(12;15) BALB͞c plasmacytomas, where most breakpoints are found near the H-DNAforming site. Thus, our findings suggest that H-DNA is a source of genetic instability resulting from DSBs and demonstrate that naturally occurring DNA sequences are mutagenic in mammals, perhaps contributing to genetic evolution and disease.

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Section: Discussionmentioning

confidence: 99%

Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells

Wang

Vásquez

2004

Proc. Natl. Acad. Sci. U.S.A.

176

179

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“…Long CTG repeats are stabilized in ColE1-derived plasmids in E. coli containing mutations in the methyl-directed mismatch repair genes (mutS, mutL, or mutH) (34). When plasmids containing (CTG) 180 were grown for about 100 generations in mutS, mutL, or mutH strains, 60 -85% of the plasmids contained a full-length repeat, whereas in the parent strain only about 20% of the plasmids contained the full-length repeat.…”

Section: Mismatch Repairmentioning

confidence: 99%

Molecular Basis of Genetic Instability of Triplet Repeats

Wells¹

1996

Journal of Biological Chemistry

302

219

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“…However, our data suggest that, once formed, ordered, single-stranded triplet repeat structures can represent local minima. Errors in the passage of the replication fork through the triplet repeat domain (10,67,68), faulty repair processes (69,70), or some other yet-to-be-determined mechanism may lead to expansion of triplet repeat DNA when such single-stranded ordered states are populated. Because the onset of the expansion of the triplet repeat domain may depend on such metastable states, the lifetime as well as the relative thermodynamic stability of the ordered structure must be considered in the regulation of events that allow expansion to occur.…”

Section: Biological Implicationsmentioning

confidence: 99%

Conformational energetics of stable and metastable states formed by DNA triplet repeat oligonucleotides: Implications for triplet expansion diseases

Völker

Makube

Plum

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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We have embedded the hexameric triplet repeats (CAG)6 and (CTG) 6 between two (GC)3 domains to produce two 30-mer hairpins with the sequences d[(GC) 3(CAG)6(GC)3] and d[(GC)3(CTG)6(GC)3]. This construct reduces the conformational space available to these repetitive DNA sequences. We find that the (CAG) 6 and (CTG)6 repeats form stable, ordered, single-stranded structures. These structures are stabilized at 62°C by an average enthalpy per base of 1.38 kcal⅐mol ؊1 for the CAG triplet and 2.87 kcal⅐mol ؊1 for the CTG triplet, while being entropically destabilized by 3.50 cal⅐K ؊1 ⅐mol ؊1 for the CAG triplet and 7.6 cal⅐K ؊1 ⅐mol ؊1 for the CTG triplet. Remarkably, these values correspond, respectively, to 1͞3 (for CAG) and 2͞3 (for CTG) of the enthalpy and entropy per base values associated with Watson-Crick base pairs. We show that the presence of the loop structure kinetically inhibits duplex formation from the two complementary 30-mer hairpins, even though the duplex is the thermodynamically more stable state. Duplex formation, however, does occur at elevated temperatures. We propose that this thermally induced formation of a more stable duplex results from thermal disruption of the single-stranded order, thereby allowing the complementary domains to associate (perhaps via "kissing hairpins"). Our melting profiles show that, once duplex formation has occurred, the hairpin intermediate state cannot be reformed, consistent with our interpretation of kinetically trapped hairpin structures. The duplex formed by the two complementary oligonucleotides does not have any unusual optical or thermodynamic properties. By contrast, the very stable structures formed by the individual single-stranded triplet repeat sequences are thermally and thermodynamically unusual. We discuss this stable, triplet repeat, single-stranded structure and its interconversion with duplex in terms of triplet expansion diseases.

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Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases.

Abstract: Long CTG triplet repeats which are associated with several human hereditary neuromuscular disease genes are stabilized in ColEl-derived

Cited by 144 publications

References 23 publications

Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells

Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells

Molecular Basis of Genetic Instability of Triplet Repeats

Conformational energetics of stable and metastable states formed by DNA triplet repeat oligonucleotides: Implications for triplet expansion diseases

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