Triplex-mediated analysis of cytosine methylation at CpA sites in DNA

Johannsen, Marie W.; Gerrard, Simon R.; Melvin, T.; Brown, Tom

doi:10.1039/c3cc45917a

Cited by 10 publications

(10 citation statements)

References 30 publications

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“…DNA triplexes have evoked potential technological applications which include creating high quality DNA vectors for human gene therapy [ 28 ], nanomachines for monitoring intracellular pH gradient [ 29 ], molecular switches [ 30 , 31 , 32 ], and for developing drug delivery systems [ 33 , 34 ]. They have also been used as biosensors for the recognition and analysis of toxic metal ions [ 35 ], SNPs [ 36 ], DNA methylation [ 37 ] and cancer cells [ 38 ]. Quite recently, DNA triplex formation process has been exploited in developing PCR based biosensor for detection of pathogens [ 39 ], high-throughput assays for measuring activity of DNA topoisomerases and other enzymes involved in DNA topology modification [ 40 ], controlled assembly of liposomes [ 41 ] and as modular probes for DNA detection [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets

2016

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Implications of DNA, RNA and RNA.DNA hybrid triplexes in diverse biological functions, diseases and therapeutic applications call for a thorough understanding of their structure-function relationships. Despite exhaustive studies mechanistic rationale for the discriminatory preference of parallel DNA triplexes with G*GC & T*AT triplets still remains elusive. Here, we show that the highest nonisostericity between the G*GC & T*AT triplets imposes extensive stereochemical rearrangements contributing to context dependent triplex destabilisation through selective disruption of Hoogsteen scheme of hydrogen bonds. MD simulations of nineteen DNA triplexes with an assortment of sequence milieu reveal for the first time fresh insights into the nature and extent of destabilization from a single (non-overlapping), double (overlapping) and multiple pairs of nonisosteric base triplets (NIBTs). It is found that a solitary pair of NIBTs, feasible either at a G*GC/T*AT or T*AT/G*GC triplex junction, does not impinge significantly on triplex stability. But two overlapping pairs of NIBTs resulting from either a T*AT or a G*GC interruption disrupt Hoogsteen pair to a noncanonical mismatch destabilizing the triplex by ~10 to 14 kcal/mol, implying that their frequent incidence in multiples, especially, in short sequences could even hinder triplex formation. The results provide (i) an unambiguous and generalised mechanistic rationale for the discriminatory trait of parallel triplexes, including those studied experimentally (ii) clarity for the prevalence of antiparallel triplexes and (iii) comprehensive perspectives on the sequence dependent influence of nonisosteric base triplets useful in the rational design of TFO’s against potential triplex target sites.

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Section: Introductionmentioning

confidence: 99%

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets

2016

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“…One group is consisting of proteins that act as binders and that are typically used in affinity enrichment assays. These can bind DNA either without or with constrained sequence selectivity (i.e., in the context of short and fixed recognition sequences such as palindromes), or they bind DNA with programmable sequence selectivity (a related potential may be offered by triplex-forming oligonucleotides) . The second group consists of proteins that act as processive readers and recognize nucleobases in a continuous manner as DNA is passing through the protein.…”

Section: New Challenges For Deciphering Epigenetic Cytosine Modificat...mentioning

confidence: 99%

Deciphering Epigenetic Cytosine Modifications by Direct Molecular Recognition

Kubik

Summerer

2015

ACS Chem. Biol.

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Epigenetic modification at the 5-position of cytosine is a key regulatory element of mammalian gene expression with important roles in genome stability, development, and disease. The repertoire of cytosine modifications has long been confined to only 5-methylcytosine (mC) but has recently been expanded by the discovery of 5-hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine. These are key intermediates of active mC demethylation but may additionally represent new epigenetic marks with distinct biological roles. This leap in chemical complexity of epigenetic cytosine modifications has not only created a pressing need for analytical approaches that enable unraveling of their functions, it has also created new challenges for such analyses with respect to sensitivity and selectivity. The crucial step of any such approach that defines its analytic potential is the strategy used for the actual differentiation of the cytosine 5-modifications from one another, and this selectivity can in principle be provided either by chemoselective conversions or by selective, molecular recognition events. While the former strategy has been particularly successful for accurate genomic profiling of cytosine modifications in vitro, the latter strategy provides interesting perspectives for simplified profiling of natural, untreated DNA, as well as for emerging applications such as single cell analysis and the monitoring of cytosine modification in vivo. We here review analytical techniques for the deciphering of epigenetic cytosine modifications with an emphasis on approaches that are based on the direct molecular recognition of these modifications in DNA.

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“…Characterising the in vivo effects of DNA methylation on G4 structures may provide a possible therapeutic avenue to further enhance specificity in the tumour environment. Additional DNA modifications, such as 8-oxoguanine [ 142 ] or methylation at CpA dinucleotides [ 143 ] can affect the structural kinetics of non B-DNA formations and have been linked to the silencing of cancer genes in lymphoma and myeloma cell lines [ 144 ]. However, the effect that these could have on non B-DNA structural formation has not attracted substantial scientific investigation.…”

Section: Introductionmentioning

confidence: 99%

The Dynamic Regulation of G-Quadruplex DNA Structures by Cytosine Methylation

Stevens

Jong

Kennedy

2022

IJMS

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It is well known that certain non B-DNA structures, including G-quadruplexes, are key elements that can regulate gene expression. Here, we explore the theory that DNA modifications, such as methylation of cytosine, could act as a dynamic switch by promoting or alleviating the structural formation of G-quadruplex structures in DNA or RNA. The interaction between epigenetic DNA modifications, G4 formation, and the 3D architecture of the genome is a complex and developing area of research. Although there is growing evidence for such interactions, a great deal still remains to be discovered. In vivo, the potential effect that cytosine methylation may have on the formation of DNA structures has remained largely unresearched, despite this being a potential mechanism through which epigenetic factors could regulate gene activity. Such interactions could represent novel mechanisms for important biological functions, including altering nucleosome positioning or regulation of gene expression. Furthermore, promotion of strand-specific G-quadruplex formation in differentially methylated genes could have a dynamic role in directing X-inactivation or the control of imprinting, and would be a worthwhile focus for future research.

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Triplex-mediated analysis of cytosine methylation at CpA sites in DNA

Cited by 10 publications

References 30 publications

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets

Deciphering Epigenetic Cytosine Modifications by Direct Molecular Recognition

The Dynamic Regulation of G-Quadruplex DNA Structures by Cytosine Methylation

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Triplex-mediated analysis of cytosine methylation at CpA sites in DNA

Cited by 10 publications

References 30 publications

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the G*GC and T*AT Triplets

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the G*GC and T*AT Triplets

Deciphering Epigenetic Cytosine Modifications by Direct Molecular Recognition

The Dynamic Regulation of G-Quadruplex DNA Structures by Cytosine Methylation

Contact Info

Product

Resources

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Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the GGC and TAT Triplets