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
listen);[1] DNA) is a thread-like chain of nucleotides 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), they are one of the four major types of macromolecules that are essential for all known forms of life. Most DNA molecules consist of two biopolymer strands coiled around each other to form a double helix.The two DNA strands are called polynucleotides since they are composed of simpler monomer 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 a DNA molecule, 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 biological 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. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes. 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 the 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]
Contents
Properties
Chemical structure of DNA; hydrogen bonds shown as dotted lines
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. These asymmetric bonds mean a strand of DNA has a direction. 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).
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, 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-hydroxymethyldeoxyuracil (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 a bacteriophage - S-2L - 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-glutamythymidine 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.
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.[45] 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.[46] 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.[47] 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.[48] 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] |
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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.
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.[49] 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.[50]
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.[51]
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.[52] 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.[53] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.[54]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.[55] 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,[56] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[57]
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.[58] 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.[59] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.[60]
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.[61]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.[62][63] 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.[64] 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,[65] it is not a well-defined conformation but a family of related DNA conformations[66] 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.[67][68]
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.[69][70] 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.[71] These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.[72]
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,[73][73][74] though the research was disputed,[74][75] and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.[76]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.[77] 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.[78] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[79]
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.[83] 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.[81]
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| 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.[84] Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.Chemical modifications and altered DNA packaging
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| cytosine | 5-methylcytosine | thymine |
Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine.
Base modifications and DNA packaging
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.[85]For one example, cytosine methylation produces 5-methylcytosine, which is important for X-inactivation of chromosomes.[86] The average level of methylation varies between organisms – the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine.[87] Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations.[88] Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain,[89] and the glycosylation of uracil to produce the "J-base" in kinetoplastids.[90][91]
Damage
A covalent adduct between a metabolically activated form of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA[92]
Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. 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.[102] As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen.[103] Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication.[104] Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells.[105]
Biological functions
Location of eukaryote nuclear DNA within the chromosomes.
Genes and genomes
Genomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.[107] The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.[108] The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species, represent a long-standing puzzle known as the "C-value enigma".[109] However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.[110]
T7 RNA polymerase (blue) producing an mRNA (green) from a DNA template (orange).[111]
Transcription and translation
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard 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 TAA, TGA, and TAG codons.
DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.
Replication
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 for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA 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.[115] 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.[116] Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer;[117] it may provide nutrients;[118] and it may act as a buffer to recruit or titrate ions or antibiotics.[119] Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm;[120] it may contribute to biofilm formation;[121] and it may contribute to the biofilm's physical strength and resistance to biological stress.[122]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.[123]
Interactions with proteins
All the functions of DNA depend on interactions with proteins. These protein 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.DNA-binding proteins
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Interaction of DNA (in orange) with histones (in blue). These proteins' basic amino acids bind to the acidic phosphate groups on DNA.
A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein 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.[131] These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
The lambda repressor helix-turn-helix transcription factor bound to its DNA target[132]
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.[135] Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular 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.[46]
DNA-modifying enzymes
Nucleases and ligases
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and makes a cut at the horizontal line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.[137] In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.Enzymes called DNA ligases can rejoin cut or broken DNA strands.[138] Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.[138]
Topoisomerases and helicases
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling 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.[59] 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.[139] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.[60]Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands.[140] These enzymes are essential for most processes where enzymes need to access the DNA bases.
Polymerases
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are called templates. 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.[141] In the active 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-dependent DNA 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 a proofreading 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.[142] In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.[143]
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres.[77][144] For example, HIV reverse transcriptase is an enzyme for AIDS virus replication.[144] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizes telomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage.[78]
Transcription is carried out by a DNA-dependent RNA 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 a messenger RNA transcript until it reaches a region of DNA called the terminator, 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 large protein complex with multiple regulatory and accessory subunits.[145]
Genetic recombination
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Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.[146]
Recombination involves the breaking and rejoining of two chromosomes (M
and F) to produce two rearranged chromosomes (C1 and C2).
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins.[148] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.[149]
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51.[150] The first step in recombination is a double-stranded break caused by either an endonuclease or damage to the DNA.[151] A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday 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.[152] 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.
Evolution
DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history 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.[153][154] RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.[155] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution 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.[156] 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.[157] 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,[158] but these claims are controversial.[159][160]Building blocks of DNA (adenine, guanine, and related organic molecules) may have been formed extraterrestrially in outer space.[161][162][163] Complex DNA and RNA organic compounds of life, including uracil, cytosine, and thymine, have also been formed in the laboratory under conditions mimicking those found in outer space, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar cosmic dust and gas clouds.[164]
Uses in technology
Genetic engineering
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector.[165] The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research,[166] or be grown in agriculture.[167][168]DNA profiling
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator.[169] This process is formally termed DNA profiling, but may also be called "genetic fingerprinting". In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA.[170] However, identification can be complicated if the scene is contaminated with DNA from several people.[171] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[172] and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[173]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 the double 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,[174] bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used in DNA 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. Normal DNA sequencing methods happen after birth, but there are new methods to test paternity while a mother is still pregnant.[175]
DNA enzymes or catalytic DNA
Deoxyribozymes, also called DNAzymes or catalytic DNA, are first discovered in 1994.[176] They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach called in vitro selection or systematic 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, and etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction.[177] 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),[176] the CA1-3 DNAzymes (copper-specific),[178] the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific).[179] 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 living cells.Bioinformatics
Bioinformatics involves the development of techniques to store, data mine, search and manipulate biological data, including DNA nucleic acid sequence data. These have led to widely applied advances in computer science, especially string searching algorithms, machine learning, and database theory.[180] 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.[181] The DNA sequence may be aligned with other DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.[182] Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human 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 by gene finding algorithms, which allow researchers to predict the presence of particular gene products and their possible functions in an organism even before they have been isolated experimentally.[183] 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
The DNA structure at left (schematic shown) will self-assemble into the structure visualized by atomic force microscopy at right. DNA nanotechnology is the field that seeks to design nanoscale structures using the molecular recognition properties of DNA molecules. Image from Strong, 2004.
History and anthropology
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, their phylogeny.[188] This field of phylogenetics is a powerful tool in evolutionary 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 from ecological genetics to anthropology; For example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.[189][190]Information storage
In a paper published in Nature in January 2013, scientists from the European Bioinformatics Institute and Agilent Technologies proposed a mechanism to use DNA's ability to code information as a means of digital data storage. The group was able to encode 739 kilobytes of data into DNA code, synthesize the actual DNA, then sequence the DNA and decode the information back to its original form, with a reported 100% accuracy. The encoded information consisted of text files and audio files. A prior experiment was published in August 2012. It was conducted by researchers at Harvard University, where the text of a 54,000-word book was encoded in DNA.[191][192]Moreover, in living cells, the storage can be turned active by enzymes. Light-gated protein domains fused to DNA processing enzymes are suitable for that task in vitro.[193][194] Fluorescent exonucleases can transmit the output according to the nucleotide they have read.[195]
History of DNA research
James Watson and Francis Crick (right), co-originators of the double-helix model, with Maclyn McCarty (left).
Pencil sketch of the DNA double helix by Francis Crick in 1953
Experimental evidence supporting the Watson and Crick model was published in a series of five articles in the same issue of Nature.[210] Of these, Franklin and Gosling's paper was the first publication of their own X-ray diffraction data and original analysis method that partly supported the Watson and Crick model;[63][211] this issue also contained an article on DNA structure by Maurice Wilkins and two of his colleagues, whose analysis and in vivo B-DNA X-ray patterns also supported the presence in vivo of the double-helical DNA configurations as proposed by Crick and Watson for their double-helix molecular model of DNA in the prior two pages of Nature.[64] In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.[212] Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.[213]
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[214] Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson–Stahl experiment.[215] Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley, and Marshall Warren Nirenberg to decipher the genetic code.[216] These findings represent the birth of molecular biology.[217]
See also
- Autosome
- Crystallography
- DNA-encoded chemical library
- DNA microarray
- DNA sequencing
- Macromolecule
- Genetic disorder
- Genetic genealogy
- Haplotype
- Comparison of nucleic acid simulation software
- Meiosis
- Mitochondrial DNA
- Nuclear DNA
- Nucleic acid double helix
- Nucleic acid notation
- Nucleic acid sequence
- Pangenesis
- Phosphoramidite
- Ribosomal DNA
- Southern blot
- X-ray scattering techniques
- Xeno nucleic acid
- RNA
- Deoxyribozyme
References
- Pray L (2008). "Discovery of DNA structure and function: Watson and Crick". Nature Education. 1 (1): 100.
Further reading
- Berry A, Watson J (2003). DNA: the secret of life. New York: Alfred A. Knopf. ISBN 0-375-41546-7.
- Calladine CR, Drew HR, Luisi BF, Travers AA (2003). Understanding DNA: the molecule & how it works. Amsterdam: Elsevier Academic Press. ISBN 0-12-155089-3.
- Carina D, Clayton J (2003). 50 years of DNA. Basingstoke: Palgrave Macmillan. ISBN 1-4039-1479-6.
- Judson HF (1979). The Eighth Day of Creation: Makers of the Revolution in Biology (2nd ed.). Cold Spring Harbor Laboratory Press. ISBN 0-671-22540-5.
- Olby RC (1994). The path to the double helix: the discovery of DNA. New York: Dover Publications. ISBN 0-486-68117-3., first published in October 1974 by MacMillan, with foreword by Francis Crick; the definitive DNA textbook, revised in 1994 with a 9-page postscript
- Micklas D (2003). DNA Science: A First Course. Cold Spring Harbor Press. ISBN 978-0-87969-636-8.
- Ridley M (2006). Francis Crick: discoverer of the genetic code. Ashland, OH: Eminent Lives, Atlas Books. ISBN 0-06-082333-X.
- Olby RC (2009). Francis Crick: A Biography. Plainview, N.Y: Cold Spring Harbor Laboratory Press. ISBN 0-87969-798-9.
- Rosenfeld I (2010). DNA: A Graphic Guide to the Molecule that Shook the World. Columbia University Press. ISBN 978-0-231-14271-7.
- Schultz M, Cannon Z (2009). The Stuff of Life: A Graphic Guide to Genetics and DNA. Hill and Wang. ISBN 0-8090-8947-5.
- Stent GS, Watson J (1980). The Double Helix: A Personal Account of the Discovery of the Structure of DNA. New York: Norton. ISBN 0-393-95075-1.
- Watson, James (2004). DNA: The Secret of Life. Random House. ISBN 978-0-09-945184-6.
- Wilkins M (2003). The third man of the double helix the autobiography of Maurice Wilkins. Cambridge, England: University Press. ISBN 0-19-860665-6.
External links
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Listen to this article (info/dl)
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- DNA at Curlie (based on DMOZ)
- DNA binding site prediction on protein
- DNA the Double Helix Game From the official Nobel Prize web site
- DNA under electron microscope
- Dolan DNA Learning Center
- Double Helix: 50 years of DNA, Nature
- Proteopedia DNA
- Proteopedia Forms_of_DNA
- ENCODE threads explorer ENCODE home page. Nature
- Double Helix 1953–2003 National Centre for Biotechnology Education
- Genetic Education Modules for Teachers—DNA from the Beginning Study Guide
- PDB Molecule of the Month DNA
- Clue to chemistry of heredity found The New York Times June 1953. First American newspaper coverage of the discovery of the DNA structure
- Olby R (January 2003). "Quiet debut for the double helix". Nature. 421 (6921): 402–5. Bibcode:2003Natur.421..402O. doi:10.1038/nature01397. PMID 12540907.
- DNA from the Beginning Another DNA Learning Center site on DNA, genes, and heredity from Mendel to the human genome project.
- The Register of Francis Crick Personal Papers 1938 – 2007 at Mandeville Special Collections Library, University of California, San Diego
- Seven-page, handwritten letter that Crick sent to his 12-year-old son Michael in 1953 describing the structure of DNA. See Crick’s medal goes under the hammer, Nature, 5 April 2013.
Languages
. Bibcode:2013arXiv1311.2545M.. PMID 26455586.. PMID 16449200.. PMID 24599069.. PMID 9482833.. PMID 10562569.. PMID 19411852.. PMID 22939620.. PMID 23174300.. PMID 26929322.. PMID 13115372.. PMID 23818176.. PMID 10733978.. PMID 10393911.. PMID 15520290.Franklin RE, Gosling RG (1953). "The structure of sodium thymonucleate fibres. II. The cylindrically symmetrical Patterson function". Acta Crystallogr. 6 (8–9): 678–85. doi:10.1107/S0365110X53001940.
. PMID 12486233.. PMID 9353250.. PMID 17012276.. PMID 16515737.. PMID 23133442.. PMID 19372393.. PMID 16479578.If we lived long enough, sooner or later we all would get cancer.
A certain irreducible background incidence of cancer is to be expected regardless of circumstances: mutations can never be absolutely avoided, because they are an inescapable consequence of fundamental limitations on the accuracy of DNA replication, as discussed in Chapter 5. If a human could live long enough, it is inevitable that at least one of his or her cells would eventually accumulate a set of mutations sufficient for cancer to develop.
. PMID 17571346.. PMID 15905142.. PMID 11827946.. PMID 11178285.. PMID 11591672.. PMID 19023416.. PMID 20598083.. PMID 23300576.. PMID 23158400.. PMID 12808131.. PMID 8336674.. PMID 11058099.. PMID 7592405.. PMID 16838012.. doi:10.1080/10409230490460765. PMID 15217990.. PMID 1372984.. PMID 21836052.. PMID 11950565.. PMID 8016106.. PMID 19684594.. PMID 25918425.. PMID 11806830.. PMID 23354052.- Albrect Kossel (1879) "Ueber Nucleïn der Hefe" Archived 17 November 2017 at the Wayback Machine. (On nuclein in yeast) Zeitschrift für physiologische Chemie, 3 : 284–291.
- Albrect Kossel (1880) "Ueber Nucleïn der Hefe II" Archived 17 November 2017 at the Wayback Machine. (On nuclein in yeast, Part 2) Zeitschrift für physiologische Chemie, 4 : 290–295.
- Albrect Kossel (1881) "Ueber die Verbreitung des Hypoxanthins im Thier- und Pflanzenreich" Archived 17 November 2017 at the Wayback Machine. (On the distribution of hypoxanthins in the animal and plant kingdoms) Zeitschrift für physiologische Chemie, 5 : 267–271.
- Albrect Kossel, Untersuchungen über die Nucleine und ihre Spaltungsprodukte [Investigations into nuclein and its cleavage products] (Strassburg, Germany: K.J. Trübne, 1881), 19 pages.
- Albrect Kossel (1882) "Ueber Xanthin und Hypoxanthin" Archived 17 November 2017 at the Wayback Machine. (On xanthin and hypoxanthin), Zeitschrift für physiologische Chemie, 6 : 422–431.
- Albrect Kossel (1883) "Zur Chemie des Zellkerns" Archived 17 November 2017 at the Wayback Machine. (On the chemistry of the cell nucleus), Zeitschrift für physiologische Chemie, 7 : 7–22.
- Albrect Kossel (1886) "Weitere Beiträge zur Chemie des Zellkerns" (Further contributions to the chemistry of the cell nucleus), Zeitschrift für Physiologische Chemie, 10 : 248–264. Available on-line at: Max Planck Institute for the History of Science, Berlin, Germany Archived 14 July 2014 at the Wayback Machine.. On p. 264, Kossel remarked presciently: "Der Erforschung der quantitativen Verhältnisse der vier stickstoffreichen Basen, der Abhängigkeit ihrer Menge von den physiologischen Zuständen der Zelle, verspricht wichtige Aufschlüsse über die elementaren physiologisch-chemischen Vorgänge." (The study of the quantitative relations of the four nitrogenous bases — [and] of the dependence of their quantity on the physiological states of the cell — promises important insights into the fundamental physiological-chemical processes.)
. PMID 13103145.- Astbury WT, Bell FO (1938). "Some recent developments in the X-ray study of proteins and related structures" (PDF). Cold Spring Harbor Symposia on Quantitative Biology. 6: 109–121. Archived from the original (PDF) on 14 July 2014.
- Astbury WT (1947). "X-ray studies of nucleic acids". Symposia of the Society for Experimental Biology (1): 66–76. PMID 20257017. Archived from the original on 5 July 2014.
- Н. К. Кольцов, "Физико-химические основы морфологии" (The physical-chemical basis of morphology) – speech given at the 3rd All-Union Meeting of Zoologist, Anatomists, and Histologists at Leningrad, U.S.S.R., 12 December 1927.
- Reprinted in: Успехи экспериментальной биологии (Advances in Experimental Biology), series B, 7 (1) : ?-? (1928).
- Reprinted in German as: Nikolaj K. Koltzoff (1928) "Physikalisch-chemische Grundlagen der Morphologie" (The physical-chemical basis of morphology), Biologisches Zentralblatt, 48 (6) : 345–369.
- In 1934, Koltsov contended that the proteins that contain a cell's genetic information replicate. See: N. K. Koltzoff (5 October 1934) "The structure of the chromosomes in the salivary glands of Drosophila," Science, 80 (2075) : 312–313. From page 313: "I think that the size of the chromosomes in the salivary glands [of Drosophila] is determined through the multiplication of genonemes. By this term I designate the axial thread of the chromosome, in which the geneticists locate the linear combination of genes; … In the normal chromosome there is usually only one genoneme; before cell-division this genoneme has become divided into two strands."
. PMID 20474956.. PMID 7968924.. PMID 19871359.. PMID 12981234.. PMID 16590258.
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