For citation purposes: Van Dyke MW, Nelson LD. Triple helix-interacting proteins and cancer. OA Molecular Oncology 2013 Apr 01;1(1):5.

Critical review


Triple helix-interacting proteins and cancer

MW Van Dyke1*, LD Nelson2

Authors affiliations

(1) Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, Georgia, USA

(2) Department of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

* Corresponding author Email:



Although most naturally occurring DNA and RNA adopt the now quite familiar double-helix structure, certain sequences can, under appropriate conditions, adopt a three-stranded, triple-helical structure. Both intramolecular and intermolecular triplexes have been described. Evidence for the existence of triplex structures in vivo is limited, although cellular proteins have been identified that avidly and specifically interact with such species. The postulated roles of triplexes and the proteins that interact with them in cancer and their potential utility as diagnostic markers are discussed in this article.


More studies will be needed before the full potential of triplex nucleic acids and their role in cancer can be realised.


Triple-helical nucleic acids

Although the right-handed double-helical structure of B-form DNA is now quite famous, having been determined in 1953 through the work of Watson and Crick among others[1,2,3], it was shortly thereafter noted that certain homopolymer DNA sequences preferentially adopted a three-stranded, triple-helical structure[4]. In this structure, the third strand lies within the major groove of the double helix, interacting with purine bases on one strand of the duplex through either Hoogsteen or reverse-Hoogsteen base pairing[5]. A schematic representation of an intermolecular triplex is shown in Figure 1A.

Triplex nucleic acids. (A) Schematic representation of an intermolecular triplex. The third strand (black) resides in the major groove of the duplex nucleic acid, hydrogen bonding to the purine-rich duplex strand. Note that the third strand may be part of a larger nucleic acid (dotted line extensions). (B) Chemical structures of T*A:T and C[+]*G:C base triplets and strand orientations present in pyrimidine motif triplexes. (C) Chemical structures of A*A:T, G*G:C, and T*A:T base triplets and strand orientations present in purine motif triplexes. An asterisk (*) indicates Hoogsteen hydrogen bonding between complementary bases; a colon (:) indicates Watson–Crick hydrogen bonding between complementary bases. Arrowhead indicates 3’ end of nucleic acid strand[48].

Two triplex motifs have been described[6,7]. In the purine motif, a purine-rich third strand binds with an antiparallel orientation relative to the complementary purine-rich acceptor strand of the duplex and the primary base triplets are G*G:C and A*A:T or T*A:T, where a colon indicates the conventional Watson–Crick base pairing present in the duplex and an asterisk reverse-Hoogsteen base pairing between bases in the third strand (G, A, or T) and purine acceptors in the target duplex. In the pyrimidine motif, a pyrimidine-rich third strand binds with a parallel orientation relative to the complementary purine-rich acceptor strand of the duplex and the primary base triplets are T*A:T and C[+]*G:C, where an asterisk indicates Hoogsteen base pairing between bases in the third strand, either thymine or protonated cytosine, and purine acceptors in the target duplex. Typical triplex DNAs range from ~10 to many tens of contiguous base triplets in length. Graphical representations of the different triplex motifs and the hydrogen bonding between nucleic acid bases are shown in Figure 1B,C.

Although most triplex structures described to date are composed exclusively of DNA, both pure RNA and mixed RNA:DNA triplex species have also been identified[8,9,10,11]. However, it should be noted that not all possible combinations of nucleic acids form stable triplexes under physiological conditions. For example, a purine motif triplex composed entirely of DNA is stable but a comparable triplex containing a single RNA strand substitution is not. Presumably this inability to form triplexes stems from structural issues regarding steric repulsion, the width of the major groove and base pitch, these factors limiting third strand accessibility to purine acceptors in the duplex. Sequence considerations are also critically important in determining the relative stability of these species, especially under physiological conditions. Thus, pyrimidine motif triplex-forming nucleic acids tend to be deficient in cytosine[12], which is not highly protonated at physiological pH given its pKa = 4.45. Similarly, purine motif triplexes are disfavoured, given the propensity for single-stranded G-rich nucleic acids to form intramolecular G-quadruplex species[13]. A listing of triplex species and their relative stability is provided in Tables 1 and 2. Note that a range of pyrimidine motif stabilities have been observed for different combinations of nucleic acids, depending on the sequence of the triplex-forming oligonucleotide being investigated. Thus, a C-rich third strand can only marginally form a pyrimidine motif D*D:D triplex, whereas a T-rich third strand forms a very stable pyrimidine motif D*D:D triplex under similar conditions.

Table 1

Purine motif triplex formation.

Table 2

Pyrimidine motif triplex formation.

Triplexes are often thought of as a separate nucleic acid molecule interacting with a target duplex. One example would be a T-rich RNA interacting with a complementary homopurine–homopyrimidine DNA duplex through intermolecular pyrimidine motif triplex formation. However, examples have been found where a homopurine–homopyrimidine DNA duplex dissociates partially into single strands (e.g. as a result of superhelical torsional strain) and one strand then forms a triplex with a proximal complementary homopurine–homopyrimidine DNA duplex present in the same molecule. These are referred to as intramolecular triplexes (Figure 2A). Both pyrimidine (H-DNA) and purine (H’-DNA) motif intramolecular triplexes have been described[14,15]. In addition, four different intramolecular triplex isomers can exist for any particular homopurine–homopyrimidine sequence, depending on which motif is involved and which half-element strand serves as the third strand (Figure 2B). Most intramolecular triplexes investigated to date have been composed entirely of DNA. However, recent studies with certain long non-coding RNAs lacking 3’ poly(A) tails (e.g. MALAT1, MENβ) have found that their intrinsic high stability results from their ability to form intramolecular pyrimidine motif RNA triplexes[16,17].

Intramolecular triplexes. (A) Schematic representation of an intramolecular triplex. The third strand (grey) resides in the major groove of the duplex nucleic acid and hydrogen bonds to the purine-rich duplex strand while its complement (white) remains primarily single-stranded. (B) Schematic representations of the four possible forms of intramolecular DNA triplexes. For H-DNA isomers H-y3 (1͇) and H-y5 (2͇), the third strand is pyrimidine-rich and originates from either the 3’ or 5’ end of an oligopyrimidine duplex strand (light grey), respectively. For H’-DNA isomers H-r3 (3͇) and H-r5 (4͇) ), the third strand is purine-rich and originates from either the 3’ or 5’ end of an oligopurine duplex strand (black), respectively[48].

Although most studies with triplexes have been performed in vitro, there is an increasing body of evidence suggesting that triplexes do exist in vivo. Immunofluorescence experiments with triplex-specific monoclonal antibodies have shown distinct staining patterns on polytene chromosomes isolated from Drosophila melanogaster[18,19]. Similarly triplex-specific antibodies exhibit multiple positive foci disseminated throughout isolated human cell nuclei[20]. Although these signals were originally thought of as evidence for intramolecular DNA*DNA:DNA triplexes, more recent studies suggest that these signals may instead reflect recognition of intermolecular RNA*DNA:DNA triplexes, which are also avidly bound by these antibodies.

Triplex-binding proteins

One line of evidence for the in vivo existence of triplex nucleic acids is the presence of endogenous proteins that specifically and avidly bind these structures. Examples of triplex-binding proteins have been found in organisms ranging from bacteria and yeast to mice and humans (Figure 3). Although the identities of several of these triplex-binding proteins are as yet unknown, for those that have been identified, many have known roles involving nucleic acids. Examples include the bacterial Tn7 protein and its role in transposon insertion[21], yeast CDP1 and chromosome segregation[22], Drosophila GAGA factor and transcriptional regulation[23], human Orc4 protein and replication[24], human XPA-RPA DNA repair complexes[25], and murine HMG proteins and a variety of DNA-dependent processes (transcription, replication, recombination and repair)[26]. Note that identified triplex-binding proteins are not limited to those that interact with DNA. Several triplex-binding proteins including the yeast ribosome-binding protein Stm1p, human pre-mRNA-binding hnRNP proteins, and human splicing factors PSF, P54nrb, U2AF65 are known RNA-binding proteins with well-established RNA-dependent biological functions in vivo[27,28,29].

Triplex-binding proteins are present in many organisms. Electrophoretic mobility shift assays were assembled containing either 0.1 nM radiolabelled purine motif triplex (A) or duplex probe (B), 2 µg poly(dI-dC) carrier DNA, and various amounts of whole cell or nuclear extracts from different organisms, as indicated. (Lane 1) control reaction, no protein. (2) 6.7 µg Escherichia coli extract. (3) 11.9 µg Dictyostelium discoideum extract. (4 & 14) 12.5 µg Saccharomyces cerevisiae extract. (5) 4.8 µg Schizosaccharomyces pombe extract. (6) 2.9 µg Drosophila melanogaster extract. (7) 15.2 µg Xenopus laevis oocyte extract. (8) 0.69 µg 3T3 mouse fibroblast nuclear extract. (9) 0.62 µg LY-apoptosis refractory mouse lymphoma nuclear extract. (10) 0.62 µg LY-apoptosis susceptible mouse lymphoma nuclear extract. (11) 0.6 µg Daudi human lymphoma nuclear extract. (12) 1.34 µg K562 human erythroleukaemia nuclear extract. (13) 4.2 µg HeLa human epithelial carcinoma nuclear extract.

Triplex structures may form in vivo. However, their presence need not always be advantageous. Intramolecular triplexes could promote undesirable recombination events or interfere with normal transcriptional controls. Thus, another aspect supporting the existence of triplex species might be the presence of proteins that destabilise these structures. RecQ-family helicases, including bacterial RecQ and human BLM and WRN, can dissociate DNA triplexes in a 3′[→]5′ direction if they initiate on a 3′ single-stranded region on the third strand[30]. In contrast, the superfamily 2 helicase FANCJ requires a 5′ single-stranded region on the third strand to dissociate triplex structures and this helicase proceeds in a 5′[→]3′ direction[31]. The absence of these proteins has been found to increase genomic instability, especially at regions having the potential to form triplex structures[32]. Finally, the nucleotide excision repair complex containing XPA can be directed to triplex structures by the associated protein RPA and thereby facilitate repair of proximal DNA photoadducts[25]. This repair, however, may only have tangential effects on triplex stability and is not the primary consequence of XPA-RPA function.


The authors have referenced some of their own studies in this article. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects in these studies gave their informed consent for their participation and use of derived materials.

Triple-helical nucleic acids and cancer

Although the existence of persistent triple-helical structures in vivo is as yet not fully endorsed by the scientific community, several lines of evidence implicating triplexes in cancer have been described. Sequences capable of forming H-DNA are abundant in mammalian genomes and these sequences often correspond to sites of increased susceptibility to chromosomal translocations (e.g. the promoter region of the c-MYC oncogene and c-MYC translocations present in several lymphomas and leukaemias)[33,34]. Both intermolecular and intramolecular DNA triplexes have been shown to be mutagenic, promoting both recombination and DNA repair. More recently, the unexpected stability of certain long non-coding RNAs involved in cancer, including Kaposi’s sarcoma-associated herpes virus polyadenylated nuclear (PAN), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and multiple endocrine neoplasia-β (MENβ) RNAs have been found to be the result of intramolecular RNA triplex formation near their 3′ ends[16,17,35].

Triplex-dissociating helicases and cancer

If triplexes exist and promote cancer, then the loss of proteins that prevent triplex formation and/or dissociate triplex structures should promote cancer. This is true for the DNA helicases BLM and WRN and for the bifunctional RNA and DNA helicase FANCJ. BLM is part of the BRCA1-associated genome surveillance complex and is normally involved in DNA replication and repair[36]. Defects in BLM are the cause of Bloom’s syndrome, characterised by proportionate prenatal and postnatal growth deficiency, sun-sensitive telangiectatic hypopigmented and hyperpigmented skin, predisposition to general malignancy and chromosomal instability[37]. WRN has both helicase and exonuclease activities and is involved in resolving inappropriate structures during recombination, DNA replication and repair[38]. Defects in WRN are the cause of Werner syndrome, characterised by the premature onset of multiple age-related disorders, including atherosclerosis, non-insulin-dependent diabetes mellitus, ocular cataracts, osteoporosis and the appearance of rare cancers (e.g. osteosarcomas and chondrosarcomas)[39]. FANCJ (also known as BRIP1 or BACH1) is also associated with BRCA1 and is normally involved in DNA double-strand break repair by homologous recombination[40]. Defects in FANCJ are the cause of Fanconi anaemia complementation group J and result in anaemia, leukopaenia and thrombopaenia. Loss of FANCJ has been described in several cancers but especially associated with breast carcinomas. However, it should be noted that while all of these helicases can act upon triplex structures, they can also act upon other non-B structures (e.g. G-quadruplex, cruciform, slipped-strands) as well as normal duplex nucleic acids[42]. Thus, it cannot be said for certain which structure’s resolution is most responsible for the effects of these helicases on cancer.

Triplex-binding proteins and cancer

With like reasoning, if triplexes exist and promote cancer, then proteins that facilitate triplex formation and/or stabilise triplex structures may promote cancer. This has been more difficult to establish for triplex-binding proteins. For example, while the human Orc4 protein plays an essential role in the initiation of replication and has been found to preferentially bind pyrimidine motif triplex DNA, overexpression of this protein has not been strongly implicated in any cancer[24,43]. Certain high mobility group proteins (e.g. HMGB1) have been reported to promote the formation of purine motif triplexes[26]. However, they are well known to interact with other nucleic acid structures, preferentially single-stranded DNA, and have paradoxical oncogenic and tumour suppressive roles in several cancers[44,45]. Finally, while RPA preferentially directs XPA to DNA damage proximal to triplexes and facilitates repair, overexpression of RPA adversely impacts homologous recombination and elevated genomic instability, suggesting that the aforementioned repair does not reduce the incidence of certain cancers[46].

The best evidence for a relationship between triplex-binding proteins and cancer can be found in the recent work of Nelson et al.[29] Examining extracts from 63 human colorectal tumour and adjacent normal tissues using an electrophoretic mobility shift assay (EMSA), they found significantly higher levels of one triplex species (H3, originally described by Musso et al.[47]) in tumour extracts than in corresponding normal tissue extracts. The ratio of H3 observed in tumour versus normal tissue (T/N) significantly correlated with lymph node disease (N-stage), metastasis and a reduction in overall survival following 65 months observation. However, similar correlations were not observed for other triplex species observed in these extracts. Using affinity chromatography, nano-scale high-performance liquid chromatography and electrospray ionisation tandem mass spectrometry, they were able to identify three proteins specifically bound to their purine motif triplex DNA probe: 100-kDa polypyrimidine-tract binding-associated splicing factor PSF, 60-kDa nuclear RNA-binding protein P54nrb, and 65-kDa U2 small nuclear RNA auxiliary factor 2 isoform b. PSF and P54nrb form heterodimers and function as RNA polymerase II-associated splicing factors. U2AF65 is also a known RNA polymerase II-associated splicing factor, involved in the recognition of degenerate pyrimidine tracts downstream of the branch point during spliceosome assembly. Involvement of U2AF65 in the H3 species was confirmed using anti-U2AF65 MC3 antibody and a super-shift EMSA experiment. The roles of PSF or P54nrb in any other EMSA species were not confirmed. Of the 63 patient samples 51 were then investigated by western blotting. This confirmed U265AF correlation with H3 levels and showed increased expression in advanced clinical stages (UICC Stage III and IV, Dukes C and D). Similar correlations could not be made with either PSF or P54nrb. Curiously, western blotting indicated a strong correlation between H3 levels and the DNA helicase WRN, suggesting coordinate regulation of triplex-stabilising and triplex-destabilising activities.


Are triplexes and/or their interacting proteins suitable markers for cancer prognosis, diagnosis or targeting? This remains an open question at this time. Multiple lines of evidence suggesting the existence of triplex nucleic acids in vivo do exist. However, they are far from conclusive. Fundamental knowledge as to the exact types of triplex present: DNA, RNA or hybrid, pyrimidine motif or purine motif, intramolecular or intermolecular, as yet remains unanswered. Once a better understanding of triplex physiology has been achieved, then studies such as those of Nelson et al. can be undertaken to directly assess the role of these structures in tumour progression for different cancers. Note that further studies of triplex-interacting proteins, both stabilising and destabilising, are still potentially worthwhile. However, regardless of the observed strength of correlations found, studies with these proteins cannot be considered conclusive proof for a role of triplexes in cancer. To date for the limited number of triplex-interacting proteins identified, all have additional described biological roles beyond those involving triplex structures. For example, triplex-disrupting helicases including BLM, WRN and FANCJ can act upon other non-B form structures, including cruciforms, D-loops, G-quadruplexes, and slipped strands. Similarly, the described triplex-binding proteins are also known to avidly bind a variety of nucleic acid structures, ranging from single strands to branched nucleic acids. Thus, the identification of proteins that specifically and exclusively recognise triplex structures is paramount. In conclusion, more studies will be needed before the full potential of triplex nucleic acids and their role in cancer can be realised.


MW Van Dyke is supported by the National Institute of General Medical Sciences (1R15GM104833-01) and was supported by a Faculty Research and Creative Activities Award from his previous institution (Western Carolina University, Cullowhee NC, USA).

Authors Contribution

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.

Competing interests

None declared.

Conflict of Interests

None declared.


All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.


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Purine motif triplex formation.

Triplex → Strand↓ D*D:D D*D:R D*R:D D*R:R R*D:D R*D:R R*R:D R*R:R
3 D D D D R R R R
Pu D D R R D D R R
Py D R D R D R D R
Stability +++ ~ ~

Pyrimidine motif triplex formation.

Triplex →Strand↓ D*D:D D*D:R D*R:D D*R:R R*D:D R*D:R R*R:D R*R:R
3 D D D D R R R R
Pu D D R R D D R R
Py D R D R D R D R
Stability ~/+++ ~/++ +++/++ ++/+++ ~/+ +/~

(D) DNA, (R) RNA, (*) Hoogsteen or reverse-Hoogsteen hydrogen bonding, (:) Watson-Crick hydrogen bonding, (3) third strand of triplex, (Pu) purine-rich strand of duplex, (Py) pyrimidine-rich strand of duplex. Relative triplex stabilities range from none (–), marginal (~), weak (+), moderate (++) to strong (+++). Multiple stabilities indicate values observed for different triplex sequences. First value is dominant among three independent investigations8,9,10.