A chromosome and itspackaged long strand of DNA unraveled. The DNA'sbase pairs encode genes, which provide functions. A human DNA can have up to 500 million base pairs with thousands of genes.
The structure of the DNAdouble helix (typeB-DNA). Theatoms in the structure are colour-coded byelement and the detailed structures of twobase pairs are shown in the bottom right.Simplified diagram
The two DNA strands are known as polynucleotides as they are composed of simplermonomeric units callednucleotides.[2][3] Each nucleotide is composed of one of fournitrogen-containingnucleobases (cytosine [C],guanine [G],adenine [A] orthymine [T]), asugar calleddeoxyribose, and aphosphate group. The nucleotides are joined to one another in a chain bycovalent bonds (known as thephosphodiester linkage) between the sugar of one nucleotide and the phosphate of the next, resulting in an alternatingsugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according tobase pairing rules (A with T and C with G), withhydrogen bonds to make double-stranded DNA. The complementary nitrogenous bases are divided into two groups, the single-ringedpyrimidines and the double-ringedpurines. In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine.
Both strands of double-stranded DNA store the samebiological information. This information isreplicated when the two strands separate. A large part of DNA (more than 98% for humans) isnon-coding, meaning that these sections do not serve as patterns forprotein sequences. The two strands of DNA run in opposite directions to each other and are thusantiparallel. Attached to each sugar is one of four types of nucleobases (orbases). It is thesequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process calledtranscription, where DNA bases are exchanged for their corresponding bases except in the case of thymine (T), for which RNA substitutesuracil (U).[4] Under thegenetic code, these RNA strands specify the sequence ofamino acids within proteins in a process calledtranslation.
Chemical structure of DNA;hydrogen bonds shown as dotted lines. Each end of the double helix has an exposed5' phosphate on one strand and an exposed3′ hydroxyl group (—OH) on the other.
DNA is a longpolymer made from repeating units callednucleotides.[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 byhydrogen bonds. Both chains are coiled around the same axis, and have the samepitch of 34ångströms (3.4 nm). The pair of chains have a radius of 10 Å (1.0 nm).[9] According to another study, when measured in a different solution, the DNA chain measured 22–26 Å (2.2–2.6 nm) wide, and one nucleotide unit measured 3.3 Å (0.33 nm) long.[10] The buoyant density of most DNA is 1.7g/cm3.[11]
DNA does not usually exist as a single strand, but instead as a pair of strands that are held tightly together.[9][12] These two long strands coil around each other, in the shape of adouble helix. The nucleotide contains both a segment of thebackbone of the molecule (which holds the chain together) and anucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called anucleoside, and a base linked to a sugar and to one or more phosphate groups is called anucleotide. Abiopolymer comprising multiple linked nucleotides (as in DNA) is called apolynucleotide.[13]
The backbone of the DNA strand is made from alternatingphosphate andsugar groups.[14] The sugar in DNA is2-deoxyribose, which is apentose (five-carbon) sugar. The sugars are joined by phosphate groups that formphosphodiester bonds between the third and fifth carbonatoms of adjacent sugar rings. These are known as the3′-end (three prime end), and5′-end (five prime end) carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms aglycosidic bond.[12]
Therefore, any DNA strand normally has one end at which there is a phosphate group attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl group attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of the 3′ and 5′ carbons along the sugar-phosphate backbone confersdirectionality (sometimes called polarity) to each DNA strand. In anucleic acid double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands areantiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime end (5′ ), and three prime end (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA andRNA is the sugar, with the 2-deoxyribose in DNA being replaced by the related pentose sugarribose in RNA.[12]
A section of DNA. The bases lie horizontally between the two spiraling strands[15] (animated version).
The DNA double helix is stabilized primarily by two forces:hydrogen bonds between nucleotides andbase-stacking interactions amongaromatic nucleobases.[16] The four bases found in DNA areadenine (A),cytosine (C),guanine (G) andthymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown foradenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine, formingA-T andG-Cbase pairs.[17][18]
Nucleobase classification
The nucleobases are classified into two types: thepurines,A andG, which are fused five- and six-memberedheterocyclic compounds, and thepyrimidines, the six-membered ringsC andT.[12] A fifth pyrimidine nucleobase,uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking amethyl group on its ring. In addition to RNA and DNA, many artificialnucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.[19]
Non-canonical bases
Modified bases occur in DNA. The first of these recognized was5-methylcytosine, which was found in thegenome ofMycobacterium tuberculosis in 1925.[20] The reason for the presence of these noncanonical bases in bacterial viruses (bacteriophages) is to avoid therestriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses.[21] Modifications of the bases cytosine and adenine, the more common and modified DNA bases, play vital roles in theepigenetic control of gene expression in plants and animals.[22]
A number of noncanonical bases are known to occur in DNA.[23] Most of these are modifications of the canonical bases plus uracil.
DNA major and minor grooves. The latter is a binding site for theHoechst stain dye 33258.
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 abinding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. The major groove is 22 ångströms (2.2 nm) wide, while the minor groove is 12 Å (1.2 nm) in width.[24] Due to the larger width of the major groove, the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such astranscription 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.[25] 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 width that would be seen if the DNA was twisted back into the ordinaryB form.
Top, aGC base pair with threehydrogen bonds. Bottom, anAT base pair with two hydrogen bonds. Non-covalent hydrogen bonds between the pairs are shown as dashed lines.
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 calledcomplementarybase pairing. Purines formhydrogen 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 (from six-carbon ring to six-carbon ring) is called a Watson-Crick base pair. DNA with highGC-content is more stable than DNA with lowGC-content. AHoogsteen base pair (hydrogen bonding the 6-carbon ring to the 5-carbon ring) is a rare variation of base-pairing.[26] As hydrogen bonds are notcovalent, 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 hightemperature.[27] 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 organisms.[7]
ssDNA vs. dsDNA
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 forG,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 temperatures, low salt and highpH (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 theGC-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 themelting temperature (also calledTm value), which is the temperature at which 50% of the double-strand molecules are converted to single-strand molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage ofGC 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 highGC-content have more strongly interacting strands, while short helices with highAT content have more weakly interacting strands.[28] In biology, parts of the DNA double helix that need to separate easily, such as theTATAATPribnow box in somepromoters, tend to have a highAT content, making the strands easier to pull apart.[29]
In the laboratory, the strength of this interaction can be measured by finding the melting temperatureTm necessary to break half of the hydrogen bonds. 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.[30]
Amount
Schematickaryogram of a human. It shows 22homologous chromosomes, both the female (XX) and male (XY) versions of thesex chromosome (bottom right), as well as themitochondrial genome (to scale at bottom left). The blue scale to the left of each chromosome pair (and the mitochondrial genome) shows its length in terms of millions of DNAbase pairs.
In humans, the total femalediploidnuclear genome per cell extends for 6.37 Gigabase pairs (Gbp), is 208.23 cm long and weighs 6.51 picograms (pg).[31] Male values are 6.27 Gbp, 205.00 cm, 6.41 pg.[31] Each DNA polymer can contain hundreds of millions of nucleotides, such as inchromosome 1. Chromosome 1 is the largest humanchromosome with approximately 220 millionbase pairs, and would be85 mm long if straightened.[32]
Ineukaryotes, in addition tonuclear DNA, there is alsomitochondrial DNA (mtDNA) which encodes certain proteins used by the mitochondria. The mtDNA is usually relatively small in comparison to the nuclear DNA. For example, thehuman mitochondrial DNA forms closed circular molecules, each of which contains 16,569[33][34] DNA base pairs,[35] with each such molecule normally containing a full set of the mitochondrial genes. Each human mitochondrion contains, on average, approximately 5 such mtDNA molecules.[35] Each humancell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500.[35] However, the amount of mitochondria per cell also varies by cell type, and anegg cell can contain 100,000 mitochondria, corresponding to up to 1,500,000 copies of the mitochondrial genome (constituting up to 90% of the DNA of the cell).[36]
ADNA sequence is called a "sense" sequence if it is the same as that of amessenger RNA copy that is translated into protein.[37] 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.[38] One proposal is that antisense RNAs are involved in regulatinggene expression through RNA-RNA base pairing.[39]
A few DNA sequences in prokaryotes and eukaryotes, and more inplasmids andviruses, blur the distinction between sense and antisense strands by havingoverlapping genes.[40] 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. Inbacteria, this overlap may be involved in the regulation of gene transcription,[41] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[42]
DNA can be twisted like a rope in a process calledDNA 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.[43] 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 byenzymes calledtopoisomerases.[44] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such astranscription andDNA replication.[45]
DNA exists in many possibleconformations that includeA-DNA,B-DNA, andZ-DNA forms, although only B-DNA and Z-DNA have been directly observed in functional organisms.[14] 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 metalions, and the presence ofpolyamines in solution.[46]
The first published reports of A-DNAX-ray diffraction patterns—and also B-DNA—used analyses based onPatterson functions that provided only a limited amount of structural information for oriented fibers of DNA.[47][48] An alternative analysis was proposed by Wilkinset al. in 1953 for thein vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares ofBessel functions.[49] In the same journal,James Watson andFrancis Crick presented theirmolecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double helix.[9]
Although theB-DNA form is most common under the conditions found in cells,[50] it is not a well-defined conformation but a family of related DNA conformations[51] that occur at the high hydration levels present in cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecularparacrystals with a significant degree of disorder.[52][53]
Compared to B-DNA, the A-DNA form is a widerright-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.[54][55] Segments of DNA where the bases have been chemically modified bymethylation may undergo a larger change in conformation and adopt theZ form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.[56] These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.[57]
For many years,exobiologists have proposed the existence of ashadow biosphere, a postulated microbialbiosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that usearsenic instead of phosphorus in DNA. A report in 2010 of the possibility in thebacteriumGFAJ-1 was announced,[58][59] though the research was disputed,[59][60] and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.[61]
DNA quadruplex formed bytelomere 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.[62]
At the ends of the linear chromosomes are specialized regions of DNA calledtelomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzymetelomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.[63] These specialized chromosome caps also help protect the DNA ends, and stop theDNA repair systems in the cell from treating them as damage to be corrected.[64] Inhuman cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[65]
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, known as aguanine tetrad, form a flat plate. These flat four-base units then stack on top of each other to form a stableG-quadruplex structure.[66] These structures are stabilized by hydrogen bonding between the edges of the bases andchelation of a metal ion in the centre of each four-base unit.[67] 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.[68] 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. Thistriple-stranded structure is called a displacement loop orD-loop.[66]
Branched DNA can form networks containing multiple branches.
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.[69] Branched DNA can be used innanotechnology to construct geometric shapes, see the section onuses in technology below.
Several artificial nucleobases have been synthesized, and successfully incorporated in the eight-base DNA analogue namedHachimoji DNA. Dubbed S, B, P, and Z, these artificial bases are capable of bonding with each other in a predictable way (S–B and P–Z), maintain the double helix structure of DNA, and be transcribed to RNA. Their existence could be seen as an indication that there is nothing special about the four natural nucleobases that evolved on Earth.[70][71] On the other hand, DNA is tightly related toRNA which does not only act as a transcript of DNA but also performs as molecular machines many tasks in cells. For this purpose it has to fold into a structure. It has been shown that to allow to create all possible structures at least four bases are required for the correspondingRNA,[72] while a higher number is also possible but this would be against the naturalprinciple of least effort.
Acidity
The phosphate groups of DNA give it similaracidic properties tophosphoric acid and it can be considered as astrong acid. It will be fully ionized at a normal cellular pH, releasingprotons which leave behind negative charges on the phosphate groups. These negative charges protect DNA from breakdown byhydrolysis by repellingnucleophiles which could hydrolyze it.[73]
Macroscopic appearance
Impure DNA extracted from an orange
Pure DNA extracted from cells forms white, stringy clumps.[74]
Structure of cytosine with and without the 5-methyl group.Deamination converts 5-methylcytosine into thymine.
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure calledchromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels ofmethylation ofcytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of thehistone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (seeChromatin remodeling). There is, further,crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.[75]
For one example, cytosine methylation produces5-methylcytosine, which is important forX-inactivation of chromosomes.[76] The average level of methylation varies between organisms—the wormCaenorhabditis elegans lacks cytosine methylation, whilevertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine.[77] Despite the importance of 5-methylcytosine, it candeaminate to leave a thymine base, so methylated cytosines are particularly prone tomutations.[78] Other base modifications include adenine methylation in bacteria, the presence of5-hydroxymethylcytosine in thebrain,[79] and theglycosylation of uracil to produce the "J-base" inkinetoplastids.[80][81]
DNA can be damaged by many sorts ofmutagens, which change theDNA sequence. Mutagens includeoxidizing agents,alkylating agents and also high-energyelectromagnetic radiation such asultraviolet light andX-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producingthymine dimers, which are cross-links between pyrimidine bases.[83] On the other hand, oxidants such asfree radicals orhydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks.[84] A typical human cell contains about 150,000 bases that have suffered oxidative damage.[85] Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can producepoint mutations,insertions,deletions from the DNA sequence, andchromosomal translocations.[86] These mutations can causecancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.[87][88] DNA damages that arenaturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.[89][90][91]
Many mutagens fit into the space between two adjacent base pairs, this is calledintercalation. Most intercalators arearomatic and planar molecules; examples includeethidium bromide,acridines,daunomycin, anddoxorubicin. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations.[92] As a result, DNA intercalators may becarcinogens, and in the case of thalidomide, ateratogen.[93] Others such asbenzo[a]pyrene diol epoxide andaflatoxin form DNA adducts that induce errors in replication.[94] Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used inchemotherapy to inhibit rapidly growingcancer cells.[95]
Biological functions
Location of eukaryotenuclear DNA within the chromosomes
DNA usually occurs as linearchromosomes ineukaryotes, andcircular chromosomes inprokaryotes. The set of chromosomes in a cell makes up itsgenome; thehuman genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes.[96] The information carried by DNA is held in thesequence of pieces of DNA calledgenes.Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matchingprotein sequence in a process calledtranslation, which depends on the same interaction between RNA nucleotides. In an alternative fashion, a cell may copy its genetic information in a process calledDNA replication. The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome.
Genomic DNA is tightly and orderly packed in the process calledDNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in thecell nucleus, with small amounts inmitochondria andchloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called thenucleoid.[97] The genetic information in a genome is held within genes, and the complete set of this information in an organism is called itsgenotype. A gene is a unit ofheredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain anopen reading frame that can be transcribed, andregulatory sequences such aspromoters andenhancers, which control transcription of the open reading frame.
In manyspecies, only a small fraction of the total sequence of thegenome encodes protein. For example, only about 1.5% of the human genome consists of protein-codingexons, with over 50% of human DNA consisting of non-codingrepetitive sequences.[98] The reasons for the presence of so muchnoncoding DNA in eukaryotic genomes and the extraordinary differences ingenome size, orC-value, among species, represent a long-standing puzzle known as the "C-value enigma".[99] However, some DNA sequences that do not code protein may still encode functionalnon-coding RNA molecules, which are involved in theregulation of gene expression.[100]
Some noncoding DNA sequences play structural roles in chromosomes.Telomeres andcentromeres typically contain few genes but are important for the function and stability of chromosomes.[64][102] An abundant form of noncoding DNA in humans arepseudogenes, which are copies of genes that have been disabled by mutation.[103] These sequences are usually just molecularfossils, although they can occasionally serve as rawgenetic material for the creation of new genes through the process ofgene duplication anddivergence.[104]
A gene is a sequence of DNA that contains genetic information and can influence thephenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines amessenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and theamino-acid sequences of proteins is determined by the rules oftranslation, known collectively as thegenetic code. The genetic code consists of three-letter 'words' calledcodons formed from a sequence of three nucleotides (e.g., ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA byRNA polymerase. This RNA copy is then decoded by aribosome that reads the RNA sequence by base-pairing the messenger RNA totransfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twentystandard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAG, TAA, and TGA codons, (UAG, UAA, and UGA on the mRNA).
Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism forDNA replication. Here, the two strands are separated and then each strand'scomplementary DNA sequence is recreated by anenzyme calledDNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix.[105] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
Extracellular nucleic acids
Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L.[106] Various possible functions have been proposed for eDNA: it may be involved inhorizontal gene transfer;[107] it may provide nutrients;[108] and it may act as a buffer to recruit or titrate ions or antibiotics.[109] Extracellular DNA acts as a functional extracellular matrix component in thebiofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm;[110] it may contribute to biofilm formation;[111] and it may contribute to the biofilm's physical strength and resistance to biological stress.[112]
Cell-free fetal DNA is found in the blood of the mother, and can be sequenced to determine a great deal of information about the developing fetus.[113]
Under the name ofenvironmental DNA eDNA has seen increased use in the natural sciences as a survey tool forecology, monitoring the movements and presence of species in water, air, or on land, and assessing an area's biodiversity.[114][115]
Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA, which allowneutrophils, a type of white blood cell, to kill extracellular pathogens while minimizing damage to the host cells.[116] The process of releasing NETs (NETosis) is a form ofprogrammed cell death that only occurs in neutrophils.[117] Dysregulation of NETosis is associated with both exquisite susceptibility to infection (e.g. extracellular bacteria) as well as autoinflammation.[118]
Interactions with proteins
All the functions of DNA depend on interactions with proteins. Theseprotein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
Interaction of DNA (in orange) withhistones (in blue). These proteins' basic amino acids bind to the acidic phosphate groups on DNA.
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure calledchromatin. In eukaryotes, this structure involves DNA binding to a complex of small basic proteins calledhistones, while in prokaryotes multiple types of proteins are involved.[119][120] The histones form a disk-shaped complex called anucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, makingionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence.[121] Chemical modifications of these basic amino acid residues includemethylation,phosphorylation, andacetylation.[122] These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible totranscription factors and changing the rate of transcription.[123] Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA.[124] These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.[125]
A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replicationprotein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination, and DNA repair.[126] These binding proteins seem to stabilize single-stranded DNA and protect it from formingstem-loops or being degraded bynucleases.
The lambda repressorhelix-turn-helix transcription factor bound to its DNA target[127]
In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the varioustranscription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription.[128] Alternatively, transcription factors can bindenzymes that modify the histones at the promoter. This changes the accessibility of the DNA template to the polymerase.[129]
As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.[130] Consequently, these proteins are often the targets of thesignal transduction processes that control responses to environmental changes orcellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.[25]
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount ofsupercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break.[44] Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix.[134] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.[45]
Helicases are proteins that are a type ofmolecular motor. They use the chemical energy innucleoside triphosphates, predominantlyadenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands.[135] These enzymes are essential for most processes where enzymes need to access the DNA bases.
Polymerases
Polymerases areenzymes that synthesize polynucleotide chains fromnucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are calledtemplates. These enzymes function by repeatedly adding a nucleotide to the 3′hydroxyl group at the end of the growing polynucleotide chain. As a consequence, all polymerases work in a 5′ to 3′ direction.[136] In theactive site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, DNA-dependentDNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand. Many DNA polymerases have aproofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′exonuclease activity is activated and the incorrect base removed.[137] In most organisms, DNA polymerases function in a large complex called thereplisome that contains multiple accessory subunits, such as theDNA clamp orhelicases.[138]
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They includereverse transcriptase, which is aviral enzyme involved in the infection of cells byretroviruses, andtelomerase, which is required for the replication of telomeres.[63][139] For example, HIV reverse transcriptase is an enzyme for AIDS virus replication.[139] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizestelomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage.[64]
Transcription is carried out by a DNA-dependentRNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into amessenger RNA transcript until it reaches a region of DNA called theterminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases,RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a largeprotein complex with multiple regulatory and accessory subunits.[140]
A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.
A DNA helix usually does not interact with other segments of DNA, and in human cells, the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".[142] This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is inchromosomal crossover which occurs duringsexual reproduction, whengenetic recombination occurs. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency ofnatural selection and can be important in the rapid evolution of new proteins.[143] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.[144]
The most common form of chromosomal crossover ishomologous recombination, where the two chromosomes involved share very similar sequences.Non-homologous recombination can be damaging to cells, as it can producechromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known asrecombinases, such asRAD51.[145] The first step in recombination is a double-stranded break caused by either anendonuclease or damage to the DNA.[146] A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least oneHolliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.[147] Only strands of like polarity exchange DNA during recombination. There are two types of cleavage: east-west cleavage and north–south cleavage. The north–south cleavage nicks both strands of DNA, while the east–west cleavage has one strand of DNA intact. The formation of a Holliday junction during recombination makes it possible for genetic diversity, genes to exchange on chromosomes, and expression of wild-type viral genomes.
DNA contains the genetic information that allows all forms of life to function, grow and reproduce. However, it is unclear how long in the 4-billion-yearhistory of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.[148][149] RNA may have acted as the central part of earlycell metabolism as it can both transmit genetic information and carry outcatalysis as part ofribozymes.[150] This ancientRNA world where nucleic acid would have been used for both catalysis and genetics may have influenced theevolution of the current genetic code based on four nucleotide bases. This would occur, since the number of different bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[151] However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible because DNA survives in the environment for less than one million years, and slowly degrades into short fragments in solution.[152] Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250 million years old,[153] but these claims are controversial.[154][155]
Ancient DNA has been recovered from ancient organisms at a timescale where genome evolution can be directly observed, including from extinct organisms up to millions of years old, such as thewoolly mammoth.[160][161]
Forensic scientists can use DNA inblood,semen,skin,saliva orhair found at acrime scene to identify a matching DNA of an individual, such as a perpetrator.[166] This process is formally termedDNA profiling, also calledDNA fingerprinting. In DNA profiling, the lengths of variable sections of repetitive DNA, such asshort tandem repeats andminisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA.[167] However, identification can be complicated if the scene is contaminated with DNA from several people.[168] DNA profiling was developed in 1984 by British geneticist SirAlec Jeffreys,[169] and first used in forensic science to convict Colin Pitchfork in the 1988Enderby murders case.[170]
The development of forensic science and the ability to now obtain genetic matching on minute samples of blood, skin, saliva, or hair has led to re-examining many cases. Evidence can now be uncovered that was scientifically impossible at the time of the original examination. Combined with the removal of thedouble jeopardy law in some places, this can allow cases to be reopened where prior trials have failed to produce sufficient evidence to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The most obvious defense to DNA matches obtained forensically is to claim that cross-contamination of evidence has occurred. This has resulted in meticulous strict handling procedures with new cases of serious crime.
DNA profiling is also used successfully to positively identify victims of mass casualty incidents,[171] bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used inDNA paternity testing to determine if someone is the biological parent or grandparent of a child with the probability of parentage is typically 99.99% when the alleged parent is biologically related to the child. UsuallyDNA sequencing are carried out after birth, but there are new methods to test paternity while a mother is still pregnant.[172]
Deoxyribozymes, also called DNAzymes or catalytic DNA, were first discovered in 1994.[173] They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach calledin vitro selection orsystematic evolution of ligands by exponential enrichment (SELEX). DNAzymes catalyze variety of chemical reactions including RNA-DNA cleavage, RNA-DNA ligation, amino acids phosphorylation-dephosphorylation, carbon-carbon bond formation, etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction.[174] The most extensively studied class of DNAzymes is RNA-cleaving types which have been used to detect different metal ions and designing therapeutic agents. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific),[173] the CA1-3 DNAzymes (copper-specific),[175] the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific).[176] The NaA43 DNAzyme, which is reported to be more than 10,000-fold selective for sodium over other metal ions, was used to make a real-time sodium sensor in cells.
Bioinformatics involves the development of techniques to store,data mine, search and manipulate biological data, including DNAnucleic acid sequence data. These have led to widely applied advances incomputer science, especiallystring searching algorithms,machine learning, anddatabase theory.[177] String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.[178] The DNA sequence may bealigned with other DNA sequences to identifyhomologous sequences and locate the specificmutations that make them distinct. These techniques, especiallymultiple sequence alignment, are used in studyingphylogenetic relationships and protein function.[179] Data sets representing entire genomes' worth of DNA sequences, such as those produced by theHuman Genome Project, are difficult to use without the annotations that identify the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified bygene finding algorithms, which allow researchers to predict the presence of particulargene products and their possible functions in an organism even before they have been isolated experimentally.[180] Entire genomes may also be compared, which can shed light on the evolutionary history of particular organism and permit the examination of complex evolutionary events.
DNA nanotechnology uses the uniquemolecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties.[182] DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based and using theDNA origami method) and three-dimensional structures in the shapes ofpolyhedra.[183]Nanomechanical devices andalgorithmic self-assembly have also been demonstrated,[184] and these DNA structures have been used to template the arrangement of other molecules such asgold nanoparticles andstreptavidin proteins.[185] DNA and other nucleic acids are the basis ofaptamers, synthetic oligonucleotide ligands for specific target molecules used in a range of biotechnology and biomedical applications.[186]
Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, theirphylogeny.[187] This field of phylogenetics is a powerful tool inevolutionary biology. If DNA sequences within a species are compared,population geneticists can learn the history of particular populations. This can be used in studies ranging fromecological genetics toanthropology.
DNA as astorage device for information has enormous potential since it has much higherstorage density compared to electronic devices. However, high costs, slow read and write times (memory latency), and insufficientreliability has prevented its practical use.[188][189]
DNA was first isolated by the Swiss physicianFriedrich Miescher who, in 1869, discovered a microscopic substance in thepus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein".[190][191] In 1878,Albrecht Kossel isolated the non-protein component of "nuclein", nucleic acid, and later isolated its five primarynucleobases.[192][193]
In 1909,Phoebus Levene identified the base, sugar, and phosphate nucleotide unit of RNA (then named "yeast nucleic acid").[194][195][196] In 1929, Levene identified deoxyribose sugar in "thymus nucleic acid" (DNA).[197] Levene suggested that DNA consisted of a string of four nucleotide units linked together through the phosphate groups ("tetranucleotide hypothesis"). Levene thought the chain was short and the bases repeated in a fixed order. In 1927,Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a template".[198][199] In 1928,Frederick Griffith in hisexperiment discovered thattraits of the "smooth" form ofPneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form.[200][201] This system provided the first clear suggestion that DNA carries genetic information.
In 1933, while studying virginsea urchin eggs,Jean Brachet suggested that DNA is found in thecell nucleus and thatRNA is present exclusively in thecytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.[202][203] In 1937,William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.[204]
By 1951,Alec Todd and collaborators at theUniversity of Cambridge had determined by biochemical methods how the backbone of DNA is structured via the successive linking of carbon atoms 3 and 5 of the sugar to phosphates. This would help to corroborate Watson and Crick's later X-ray structural work.[208] Todd would later be awarded the 1957Nobel Prize in Chemistry for this and other discoveries related to DNA.[209]
Photo 51, showing X-ray diffraction pattern of DNA
In May 1952,Raymond Gosling, a graduate student working under the supervision ofRosalind Franklin, took anX-ray diffraction image, labeled as "Photo 51",[211] at high hydration levels of DNA. This photo was given to Watson and Crick byMaurice Wilkins and was critical to their obtaining the correct structure of DNA. Franklin told Crick and Watson that the backbones had to be on the outside. Before then, Linus Pauling, and Watson and Crick, had erroneous models with the chains inside and the bases pointing outwards. Franklin's identification of thespace group for DNA crystals proved her correct.[212] In February 1953,Linus Pauling andRobert Corey proposed a model for nucleic acids containing three intertwined chains, with the phosphates near the axis, and the bases on the outside.[213] Watson and Crick completed their model, which is now accepted as the first correct model of the double helix ofDNA. On 28 February 1953 Crick interrupted patrons' lunchtime atThe Eaglepub in Cambridge, England to announce that he and Watson had "discovered the secret of life".[214]
Pencil sketch of the DNA double helix by Francis Crick in 1953
The 25 April 1953 issue of the journalNature published a series of five articles giving the Watson and Crick double-helix structure DNA and evidence supporting it.[215] The structure was reported in a letter titled "MOLECULAR STRUCTURE OF NUCLEIC ACIDS A Structure for Deoxyribose Nucleic Acid", in which they said, "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."[9] This letter was followed by a letter from Franklin and Gosling, which was the first publication of their own X-ray diffraction data and of their original analysis method.[48][216] Then followed a letter by Wilkins and two of his colleagues, which contained an analysis ofin vivo B-DNA X-ray patterns, and which supported the presencein vivo of the Watson and Crick structure.[49]
In April 2023, scientists, based on new evidence, concluded that Rosalind Franklin was a contributor and "equal player" in the discovery process of DNA, rather than otherwise, as may have been presented subsequently after the time of the discovery.[217][218][219] In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received theNobel Prize in Physiology or Medicine.[220] Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.[221]
In an influential presentation in 1957, Crick laid out thecentral dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[222] Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through theMeselson–Stahl experiment.[223] Further work by Crick and co-workers showed that the genetic code was based on non-overlapping triplets of bases, calledcodons, allowingHar Gobind Khorana,Robert W. Holley, andMarshall Warren Nirenberg to decipher the genetic code.[224] These findings represent the birth ofmolecular biology.[225]
In 1986, DNA analysis was first used in a criminal investigation when police in the UK requestedAlec Jeffreys of the University of Leicester to prove or disprove the involvement in a particular case of a suspect who claimed innocence in the matter. Although the suspect had already confessed to committing a recent rape-murder, he was denying any involvement in a similar crime committed three years earlier. Yet the details of the two cases were so alike that the police concluded both crimes had been committed by the same person. However, all charges against the suspect were dropped when Jeffreys' DNA testing exonerated the suspect — from both the earlier murder and the one to which he'd confessed. Further such DNA profiling led to positive identification of another suspect (Colin Pitchfork) who, in 1988, was found guilty of both rape-murders.[226][227]
See also
Autosome – Any chromosome other than a sex chromosome
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