Triple-stranded DNA
Encyclopedia
A triple-stranded DNA is a structure of DNA
in which three oligonucleotides wind around each other and form a triple helix
. In this structure, one strand binds to a B-form DNA
double helix through Hoogsteen or reversed Hoogsteen hydrogen bonds
.
For example, a nucleobase
T binds to a Watson–Crick base-pairing
of T-A by Hoogsteen hydrogen bonds
between an AxT pair (x represents a Hoogsteen base pair
). An N-3 protonated cytosine
, represented as C+, can also form a base-triplet with a C-G pair through the Hoogsteen base-pairing
of an GxC+. Thus, the triple-helical DNAs using these Hoogsteen pairing
s consist of two homopyrimidine
s and one homopurine
, and the homopyrimidine
third strand is parallel to the homopurine
strand.
A homopurine
third strand can also bind to a homopurine
-homopyrimidine
duplex using reversed Hoogsteen pattern
s. In this triplex, a nucleobase
A binds to a T-A base pair and a G to a C-G pair. Since the nucleobase
s on the third strand have to be reversed, the homopurine
third strand is antiparallel to the homopurine
strand of the original duplex.
Triple-stranded DNA was a common hypothesis in the 1950s when scientists were struggling to discover DNA's true structural from. Watson and Crick (who later won the Nobel Prize for their double-helix model) originally considered a triple-helix model, as did Pauling
and Corey
, who published a proposal for their triple-helix model in the 1953 scientific journal Nature, as well as fellow scientist Fraser. However, Watson and Crick soon identified several problems with these models:
Fraser's model differed from Pauling and Corey's in that in his model the phosphates are on the outside and the bases are on the inside, linked together by hydrogen bonds. However, Watson and Crick found Fraser's model to be too ill-defined to comment specifically on its inadequacies in their publication in "Nature" (1953): Molecular Structure of Nucleic Acids.
Triple-stranded DNA was also described in 1957, when it was thought to occur in only one in vivo
biological process: as an intermediate product during the action of the E. coli recombination enzyme RecA
. Its role in that process is not understood.
Using nucleic acid segments that bind to the DNA duplexes to form triple strands as a way of regulating gene expression is under investigation by biotechnology companies. Similar work is also being undertaken at Yale University
.
Triple-stranded DNA has been implicated in the regulation of several genes. One, the c-myc gene has been extensively mutated to examine the exact role that triplex DNA structure, versus linear sequence, plays in gene regulation. A c-myc promoter element, termed the nuclease-sensitive element or NSE, can form tandem intramolecular triplexes of the H-DNA type and has a repeating sequence motif (ACCCTCCCC)4. The NSE when mutated and examined for transcriptional activity and for intra- and intermolecular triplex forming ability. The transcriptional activity of mutant NSEs can be predicted by the element's ability to form H-DNA and not by repeat number, position, or the number of mutant base pairs. DNA may therefore be a dynamic participant in the transcription of the c-myc gene.
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
in which three oligonucleotides wind around each other and form a triple helix
Triple helix
In geometry, a triple helix is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. Structures in the form of a triple helix include:* collagen helix...
. In this structure, one strand binds to a B-form DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
double helix through Hoogsteen or reversed Hoogsteen hydrogen bonds
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
.
For example, a nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
T binds to a Watson–Crick base-pairing
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
of T-A by Hoogsteen hydrogen bonds
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
between an AxT pair (x represents a Hoogsteen base pair
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
). An N-3 protonated cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
, represented as C+, can also form a base-triplet with a C-G pair through the Hoogsteen base-pairing
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
of an GxC+. Thus, the triple-helical DNAs using these Hoogsteen pairing
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
s consist of two homopyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
s and one homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
, and the homopyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
third strand is parallel to the homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
strand.
A homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
third strand can also bind to a homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
-homopyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
duplex using reversed Hoogsteen pattern
Hoogsteen base pair
A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases on each strand can be held together by hydrogen bonds in the major groove...
s. In this triplex, a nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
A binds to a T-A base pair and a G to a C-G pair. Since the nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
s on the third strand have to be reversed, the homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
third strand is antiparallel to the homopurine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
strand of the original duplex.
Triple-stranded DNA was a common hypothesis in the 1950s when scientists were struggling to discover DNA's true structural from. Watson and Crick (who later won the Nobel Prize for their double-helix model) originally considered a triple-helix model, as did Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
and Corey
Robert Corey
Robert Brainard Corey was an American biochemist, mostly known for his role in discovery of the α-helix and the β-sheet with Linus Pauling. Also working with Pauling was Herman Branson. Their discoveries were remarkably correct, with even the bond lengths being accurate until about 40 years later...
, who published a proposal for their triple-helix model in the 1953 scientific journal Nature, as well as fellow scientist Fraser. However, Watson and Crick soon identified several problems with these models:
- Negatively charged phosphates near the axis will repel each other, leaving the question as to how the three-chain structure would stay together.
- In a triple-helix model (specifically Pauling and Corey's model), some of the van der Waals distances appear to be too small.
Fraser's model differed from Pauling and Corey's in that in his model the phosphates are on the outside and the bases are on the inside, linked together by hydrogen bonds. However, Watson and Crick found Fraser's model to be too ill-defined to comment specifically on its inadequacies in their publication in "Nature" (1953): Molecular Structure of Nucleic Acids.
Triple-stranded DNA was also described in 1957, when it was thought to occur in only one in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
biological process: as an intermediate product during the action of the E. coli recombination enzyme RecA
RecA
RecA is a 38 kilodalton Escherichia coli protein essential for the repair and maintenance of DNA. RecA has a structural and functional homolog in every species in which it has been seriously sought and serves as an archetype for this class of homologous DNA repair proteins...
. Its role in that process is not understood.
Using nucleic acid segments that bind to the DNA duplexes to form triple strands as a way of regulating gene expression is under investigation by biotechnology companies. Similar work is also being undertaken at Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
.
Triple-stranded DNA has been implicated in the regulation of several genes. One, the c-myc gene has been extensively mutated to examine the exact role that triplex DNA structure, versus linear sequence, plays in gene regulation. A c-myc promoter element, termed the nuclease-sensitive element or NSE, can form tandem intramolecular triplexes of the H-DNA type and has a repeating sequence motif (ACCCTCCCC)4. The NSE when mutated and examined for transcriptional activity and for intra- and intermolecular triplex forming ability. The transcriptional activity of mutant NSEs can be predicted by the element's ability to form H-DNA and not by repeat number, position, or the number of mutant base pairs. DNA may therefore be a dynamic participant in the transcription of the c-myc gene.