DNA triple helices: Biological consequences and therapeutic potential

Abstract

DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a longstanding goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplexrelated gene targeting strategies for biotechnological and potential clinical applications.

DNA energy landscapes via calorimetric detection of microstate ensembles of metastable macrostates and triplet repeat diseases

“…It can be envisioned that discrete substates within the native state ensemble play important roles in the biology of other non-B-DNA secondary structures, such as G-quadruplexes (55-57), iDNAs (58-61), cruciforms (62)(63)(64), and triple helical H-DNA like structures (65)(66)(67)(68)(69)(70), inter alia (41,67,(71)(72)(73)(74)(75)(76). Given the diverse range of secondary structural elements and highly folded 3 dimensional structures common to many biologically important macromolecules, the realization of rough energy landscapes and discrete microstates for nucleic acids should prove important for understanding the broad range of mechanisms that modulate nucleic acid biology.…”

Theoretical Study of the Structural and Energetics Properties of the Interaction Sides of Guanine and Adenine in Gg and Aa Trans Base Pairs

“…Both GG II and AA II pairs have been observed in triplex structures formed by DNA and a third strand of oligonucleotide (DNA or RNA), where groups -NH 2 of both Guanines are occupied in the formation of hydrogen bonds and the O6 of Guanine and N7 of Adenine are located towards the minor and major groove respectively 24,25 , allowing the inclusion of divalent metal ions 3 . The inclusion of antiviral drugs and antibiotics is produced in areas of DNA with high concentrations of AT base pair, where the -NH 2 group is absent; in fact neomycin stabilizes DNA triplex structure with TAT bases triples 3,5,25 .…”

“…Although GG pair does not participate directly in that kind of recognition, it has been suggested that N7 and O6 atoms of the GG and GA pairs form polar hydrogen bonds with aminoglycoside antibiotics 2,[20][21][22] . These drugs are also inserted in DNA triplex structures 23,24 , where N7 and O6 atoms are found available in the purine bases of the third strand oligonucleotide 25 . In these complex structures, most likely associated with DNA repairing processes, it also observed that the Hoogsteen sides of the DNA nitrogen bases form hydrogen bonds with the WC sides of the third strand of DNA, forming the GG and AA pairs 23,24 .…”

“…These drugs are also inserted in DNA triplex structures 23,24 , where N7 and O6 atoms are found available in the purine bases of the third strand oligonucleotide 25 . In these complex structures, most likely associated with DNA repairing processes, it also observed that the Hoogsteen sides of the DNA nitrogen bases form hydrogen bonds with the WC sides of the third strand of DNA, forming the GG and AA pairs 23,24 . The orientation of glycosidic bonds in the different non canonical base pairs also plays an important role in relation to the structure and function of the nucleic acids, where the cis interactions show a negative propeller unlike trans pairs where no preference is observed and it conformational flexibility is reduced by the triple base formation 26,27 .…”

Chemical Modification of Oligonucleotides: A Novel Approach Towards Gene Targeting

“…In antigene technology, a single-stranded homopyrimidine triplex-forming oligonucleotide (TFO) added from outside may bind with homopurinehomopyrimidine stretch in target duplex DNA by Hoogsteen hydrogen bonding to form pyrimidine motif triplex, where T•A:T and C + •G:C base triplets are formed [3,4]. The formed triplex inhibits RNA polymerase and transcription factors-mediated transcription of target gene due to its steric hindrance, which may result in downregulation of expression level of target gene [3,4].…”