Interaction of DAPI with individual strands of trinucleotide repeats

Trotta, Edoardo; Grosso, N. Del; Erba, Maura; Melino, Sonia; Cicero, Daniel O.; Paci, Maurizio

doi:10.1046/j.1432-1033.2003.03877.x

Cited by 15 publications

(8 citation statements)

References 38 publications

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“…Consistent with this, a typical expansion feature of AAT•TTA triplet repeats was found in an in vitro amplification assay [9], [10], [13], [14], [15], [16], [17], [18]. Moreover, in human populations similar instabilities of AAT•TTA triplet repeats were recently found to be associated with the high IgE blood syndrome in Chinese children [19], with schizophrenia [20], [21], cocaine addiction [22], and with the high prevalence of depression in adult Parkinson's disease patients [23].…”

Section: Introductionsupporting

confidence: 77%

Transcription of AAT•ATT Triplet Repeats in Escherichia coli Is Silenced by H-NS and IS1E Transposition

et al. 2010

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BackgroundThe trinucleotide repeats AAT•ATT are simple DNA sequences that potentially form different types of non-B DNA secondary structures and cause genomic instabilities in vivo.Methodology and Principal FindingsThe molecular mechanism underlying the maintenance of a 24-triplet AAT•ATT repeat was examined in E.coli by cloning the repeats into the EcoRI site in plasmid pUC18 and into the attB site on the E.coli genome. Either the AAT or the ATT strand acted as lagging strand template in a replication fork. Propagations of the repeats in either orientation on plasmids did not affect colony morphology when triplet repeat transcription using the lacZ promoter was repressed either by supplementing LacIQ in trans or by adding glucose into the medium. In contrast, transparent colonies were formed by inducing transcription of the repeats, suggesting that transcription of AAT•ATT repeats was toxic to cell growth. Meanwhile, significant IS1E transposition events were observed both into the triplet repeats region proximal to the promoter side, the promoter region of the lacZ gene, and into the AAT•ATT region itself. Transposition reversed the transparent colony phenotype back into healthy, convex colonies. In contrast, transcription of an 8-triplet AAT•ATT repeat in either orientation on plasmids did not produce significant changes in cell morphology and did not promote IS1E transposition events. We further found that a role of IS1E transposition into plasmids was to inhibit transcription through the repeats, which was influenced by the presence of the H-NS protein, but not of its paralogue StpA.Conclusions and SignificanceOur findings thus suggest that the longer AAT•ATT triplet repeats in E.coli become vulnerable after transcription. H-NS and its facilitated IS1E transposition can silence long triplet repeats transcription and preserve cell growth and survival.

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Section: Introductionsupporting

confidence: 77%

Transcription of AAT•ATT Triplet Repeats in Escherichia coli Is Silenced by H-NS and IS1E Transposition

et al. 2010

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“…The sequence is A-T rich and may have unusual helical parameters that could diminish MMR. For example, sequences containing larger numbers of ATT repeats can form a non-hydrogen bonded structure [37], and can be induced into hairpins by the DNA minor groove binding ligand DAPI (4′,6-diamidino-2-phenylindole) [38], [39]. Triplet repeat sequences can form non-B-DNA structures that bind MMR proteins (reviewed in [30]), and they are often associated with genome instability (reviewed in [40]), albeit characterized by indels rather than base substitutions.…”

Section: Discussionmentioning

confidence: 99%

Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity

et al. 2012

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The two DNA strands of the nuclear genome are replicated asymmetrically using three DNA polymerases, α, δ, and ε. Current evidence suggests that DNA polymerase ε (Pol ε) is the primary leading strand replicase, whereas Pols α and δ primarily perform lagging strand replication. The fact that these polymerases differ in fidelity and error specificity is interesting in light of the fact that the stability of the nuclear genome depends in part on the ability of mismatch repair (MMR) to correct different mismatches generated in different contexts during replication. Here we provide the first comparison, to our knowledge, of the efficiency of MMR of leading and lagging strand replication errors. We first use the strand-biased ribonucleotide incorporation propensity of a Pol ε mutator variant to confirm that Pol ε is the primary leading strand replicase in Saccharomyces cerevisiae. We then use polymerase-specific error signatures to show that MMR efficiency in vivo strongly depends on the polymerase, the mismatch composition, and the location of the mismatch. An extreme case of variation by location is a T-T mismatch that is refractory to MMR. This mismatch is flanked by an AT-rich triplet repeat sequence that, when interrupted, restores MMR to >95% efficiency. Thus this natural DNA sequence suppresses MMR, placing a nearby base pair at high risk of mutation due to leading strand replication infidelity. We find that, overall, MMR most efficiently corrects the most potentially deleterious errors (indels) and then the most common substitution mismatches. In combination with earlier studies, the results suggest that significant differences exist in the generation and repair of Pol α, δ, and ε replication errors, but in a generally complementary manner that results in high-fidelity replication of both DNA strands of the yeast nuclear genome.

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“…Moreover, it was shown that DAPI stalls replication of the (AT T) 10 template by the Klenow fragment of DNA polymerase I, presumably due to hairpin formation. 168 This demonstrates that drug binding to mismatch sites can result in conformation changes of the DNA strands, leading to modulation of biological properties.…”

Section: Melamine-intercalator Conjugates and Analoguesmentioning

confidence: 99%

Finding needles in a basestack: recognition of mismatched base pairs in DNA by small molecules

2014

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Mismatched (non-Watson-Crick) base pairs represent the most common type of DNA damage, as they are permanently formed in living cells due to erroneous insertion, deletion and misincorporation of bases. In vivo, they are readily recognised and repaired by the proteins of the DNA mismatch repair system, which identify the mismatch sites with high efficiency and fidelity. Notably, the last decades have witnessed the development of several chemically diverse families of small organic molecules and metal complexes that selectively bind to mismatched base pairs (and not to fully paired double-stranded DNA), much like the proteins of the mismatch repair system. This review focuses on these DNA mismatch-binding ligands, with an emphasis on their (often unusual) binding modes, as well as on the similarities and differences between the different classes of mismatch binders. Also discussed are the potential bioanalytical and therapeutic applications of mismatch-binding ligands.

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Interaction of DAPI with individual strands of trinucleotide repeats

Cited by 15 publications

References 38 publications

Transcription of AAT•ATT Triplet Repeats in Escherichia coli Is Silenced by H-NS and IS1E Transposition

Transcription of AAT•ATT Triplet Repeats in Escherichia coli Is Silenced by H-NS and IS1E Transposition

Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity

Finding needles in a basestack: recognition of mismatched base pairs in DNA by small molecules

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