DNA

The structure of the DNA double helix. The atoms in the structure are colour-coded by element and the detailed structures of two base pairs are shown in the bottom right.
The structure of part of a DNA double helix

Deoxyribonucleic acid (-/ (About this sound listen);[1] DNA) is a molecule composed of two chains (made of nucleotides) that coil around each other to form a double helix carrying the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

The two DNA strands are also known as polynucleotides since they are composed of simpler monomeric units called nucleotides.[2][3] Each nucleotide is composed of one of four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA.

The complementary nitrogenous bases are divided into two groups, pyrimidines and purines. In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine.

DNA stores biological information. The DNA backbone is resistant to cleavage, and both strands of the double-stranded structure store the same biological information. This information is replicated as and when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences.

The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (informally, bases). It is the sequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process called transcription. Under the genetic code, these RNA strands are translated to specify the sequence of amino acids within proteins in a process called translation.

Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms (animals, plants, fungi and protists) store most of their DNA inside the cell nucleus and some of their DNA in organelles, such as mitochondria or chloroplasts.[4] In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm. Within eukaryotic chromosomes, chromatin proteins, such as histones, compact and organize DNA. These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.

DNA was first isolated by Friedrich Miescher in 1869. Its molecular structure was first identified by James Watson and Francis Crick at the Cavendish Laboratory within the University of Cambridge in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Raymond Gosling, who was a post-graduate student of Rosalind Franklin. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity. The unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNA origami and DNA-based hybrid materials.[5]

Properties

Chemical structure of DNA; hydrogen bonds shown as dotted lines

DNA is a long polymer made from repeating units called nucleotides.[6][7] The structure of DNA is dynamic along its length, being capable of coiling into tight loops, and other shapes.[8] In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled round the same axis, and have the same pitch of 34 ångströms (3.4 nanometres). The pair of chains has a radius of 10 ångströms (1.0 nanometre).[9] According to another study, when measured in a different solution, the DNA chain measured 22 to 26 ångströms wide (2.2 to 2.6 nanometres), and one nucleotide unit measured 3.3 Å (0.33 nm) long.[10] Although each individual nucleotide repeating unit is very small, DNA polymers can be very large molecules containing millions to hundreds of millions of nucleotides. For instance, the DNA in the largest human chromosome, chromosome number 1, consists of approximately 220 million base pairs[11] and would be 85 mm long if straightened.

In living organisms, DNA does not usually exist as a single molecule, but instead as a pair of molecules that are held tightly together.[12][13] These two long strands entwine like vines, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. A polymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide.[14]

The backbone of the DNA strand is made from alternating phosphate and sugar residues.[15] The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings, which are known as the 3′ and 5′ carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond. When imagining DNA, each phosphoryl is normally considered to "belong" to the nucleotide whose 5′ carbon forms a bond therewith. Any DNA strand therefore normally has one end at which there is a phosphoryl attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of the 3′ and 5′ carbons along the sugar-phosphate backbone confers directionality (sometimes called polarity) to each DNA strand. In a double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime (5′) and three prime (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the alternative pentose sugar ribose in RNA.[13]

A section of DNA. The bases lie horizontally between the two spiraling strands[16] (animated version).

The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases.[17] In the aqueous environment of the cell, the conjugated π bonds of nucleotide bases align perpendicular to the axis of the DNA molecule, minimizing their interaction with the solvation shell. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine. It was represented by A-T base pairs and G-C base pairs.[18][19]

Nucleobase classification

The nucleobases are classified into two types: the purines, A and G, being fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T.[13] A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.[20]

Non canonical bases

Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine. However, in several bacteriophages, such as Bacillus subtilis bacteriophages PBS1 and PBS2 and Yersinia bacteriophage piR1-37, thymine has been replaced by uracil.[21] Another phage - Staphylococcal phage S6 - has been identified with a genome where thymine has been replaced by uracil.[22]

5-hydroxymethyldeoxyuridine,(hm5dU) is also known to replace thymidine in several genomes including the Bacillus phages SPO1, ϕe, SP8, H1, 2C and SP82. Another modified uracil - 5-dihydroxypentauracil – has also been described.[23]

Base J (beta-d-glucopyranosyloxymethyluracil), a modified form of uracil, is also found in several organisms: the flagellates Diplonema and Euglena, and all the kinetoplastid genera.[24] Biosynthesis of J occurs in two steps: in the first step, a specific thymidine in DNA is converted into hydroxymethyldeoxyuridine; in the second, HOMedU is glycosylated to form J.[25] Proteins that bind specifically to this base have been identified.[26][27][28] These proteins appear to be distant relatives of the Tet1 oncogene that is involved in the pathogenesis of acute myeloid leukemia.[29] J appears to act as a termination signal for RNA polymerase II.[30][31]

In 1976, the S-2La bacteriophage, which infects species of the genus Synechocystis, was found to have all the adenosine bases within its genome replaced by 2,6-diaminopurine.[32] In 2016 deoxyarchaeosine was found to be present in the genomes of several bacteria and the Escherichia phage 9g.[33]

Modified bases also occur in DNA. The first of these recognised was 5-methylcytosine, which was found in the genome of Mycobacterium tuberculosis in 1925.[34] The complete replacement of cytosine by 5-glycosylhydroxymethylcytosine in T even phages (T2, T4 and T6) was observed in 1953[35] In the genomes of Xanthomonas oryzae bacteriophage Xp12 and halovirus FH the full complement of cystosine has been replaced by 5-methylcytosine.[36][37] 6N-methyadenine was discovered to be present in DNA in 1955.[38] N6-carbamoyl-methyladenine was described in 1975.[39] 7-methylguanine was described in 1976.[40] N4-methylcytosine in DNA was described in 1983.[41] In 1985 5-hydroxycytosine was found in the genomes of the Rhizobium phages RL38JI and N17.[42] α-putrescinylthymine occurs in both the genomes of the Delftia phage ΦW-14 and the Bacillus phage SP10.[43] α-glutamylthymidine is found in the Bacillus phage SP01 and 5-dihydroxypentyluracil is found in the Bacillus phage SP15.

The reason for the presence of these non canonical bases in DNA is not known. It seems likely that at least part of the reason for their presence in bacterial viruses (phages) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses.

This does not appear to be the entire story. Four modifications to the cytosine residues in human DNA have been reported.[44] These modifications are the addition of methyl (CH3)-, hydroxymethyl (CH2OH)-, formyl (CHO)- and carboxyl (COOH)- groups. These modifications are thought to have regulatory functions.

Uracil is found in the centromeric regions of at least two human chromosomes (6 and 11).[45]

Listing of non canonical bases found in DNA

Seventeen non canonical bases are known to occur in DNA. Most of these are modifications of the canonical bases plus uracil.

  • Modified Adenosine
    • N6-carbamoyl-methyladenine
    • N6-methyadenine
  • Modified Guanine
    • 7-Methylguanine
  • Modified Cytosine
    • N4-Methylcytosine
    • 5-Carboxylcytosine
    • 5-Formylcytosine
    • 5-Glycosylhydroxymethylcytosine
    • 5-Hydroxycytosine
    • 5-Methylcytosine
  • Modified Thymidine
    • α-Glutamythymidine
    • α-Putrescinylthymine
  • Uracil and modifications
    • Base J
    • Uracil
    • 5-Dihydroxypentauracil
    • 5-Hydroxymethyldeoxyuracil
  • Others
    • Deoxyarchaeosine
    • 2,6-Diaminopurine
DNA major and minor grooves. The latter is a binding site for the Hoechst stain dye 33258.

Grooves

Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. One groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide.[46] The width of the major groove means that the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove.[47] This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.

Base pairing

In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix is called a Watson-Crick base pair. Another type of base pairing is Hoogsteen base pairing where two hydrogen bonds form between guanine and cytosine.[48] As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature.[49] As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[7]

Base pair GC.svg
Base pair AT.svg
Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent hydrogen bonds between the pairs are shown as dashed lines.

The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, right). DNA with high GC-content is more stable than DNA with low GC-content.

As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double-stranded (dsDNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart – a process known as melting – to form two single-stranded DNA (ssDNA) molecules. Melting occurs at high temperature, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).

The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the "melting temperature", which is the temperature at which 50% of the ds molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.[50] In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.[51]

In the laboratory, the strength of this interaction can be measured by finding the temperature necessary to break the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.[52]

Sense and antisense

A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into protein.[53] The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear.[54] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.[55]

A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes.[56] In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[57] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[58]

Supercoiling

DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.[59] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.[60] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.[61]

From left to right, the structures of A, B and Z DNA

Alternative DNA structures

DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have been directly observed in functional organisms.[15] The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution.[62]

The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA.[63][64] An alternative analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions.[65] In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double-helix.[9]

Although the B-DNA form is most common under the conditions found in cells,[66] it is not a well-defined conformation but a family of related DNA conformations[67] that occur at the high hydration levels present in living cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder.[68][69]

Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes.[70][71] Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.[72] These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.[73]

Alternative DNA chemistry

For many years, exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1, was announced,[74][74][75] though the research was disputed,[75][76] and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.[77]

Quadruplex structures

At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.[78] These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected.[79] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[80]

DNA quadruplex formed by telomere repeats. The looped conformation of the DNA backbone is very different from the typical DNA helix. The green spheres in the center represent potassium ions.[81]

These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.[82] These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit.[83] Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.

In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins.[84] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.[82]

Branch-dna-single.svg Branch-DNA-multiple.svg
Single branch Multiple branches
Branched DNA can form networks containing multiple branches.

Branched DNA

In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible.[85] Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.

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