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{{short description|Branched nucleic acid structure}}
{{good article}}
[[File:Неподвижная структура Холлидея (англ.).svg|thumb| Schematic of a Holliday
A '''Holliday junction''' is a branched [[nucleic acid]] structure that contains four double-stranded arms joined
In biology, Holliday junctions are a key intermediate in many types of [[genetic recombination]], as well as in [[DNA repair#Double-strand breaks|double-strand break repair]]. These junctions usually have a symmetrical sequence and are thus mobile, meaning that the four individual arms may [[Branch migration|slide]] through the junction in a specific pattern that largely preserves [[base pair]]ing. Additionally, four-arm junctions similar to Holliday junctions appear in some [[Non-coding RNA|functional RNA]] molecules.
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== Structure ==
{{multiple image | image1=Holliday junction.jpg | caption1=Molecular structure of a stacked Holliday junction, in which the four arms stack into two double-helical domains. Note how the blue and red strands remain roughly helical, while the green and yellow strands cross over between the two domains. | image2=Holliday junction coloured.png | caption2=Molecular structure of an unstacked (open-X) Holliday junction. This conformation lacks [[base stacking]] between the double-helical domains, and is stable only in solutions lacking divalent metal ions such as [[Magnesium|Mg]]<sup>2+</sup>. From {{PDB
[[File:Holliday junction stacking isomers.svg|thumb| Schematic diagrams of the three base-stacking [[conformational isomer]]s of the Holliday junction. The two stacked conformers differ in which sets of two arms are bound by [[coaxial stacking]]: at left, the stacks are red–blue and cyan–magenta, while at right the stacks are red–cyan and blue–magenta. The bases nearest to the junction point determine which stacked isomer dominates.]]
Holliday junctions may exist in a variety of [[conformational isomer]]s with different patterns of [[coaxial stacking]] between the four double-helical arms. Coaxial stacking is the tendency of nucleic acid [[Sticky and blunt ends|blunt end]]s to bind to each other, by interactions between the exposed bases. There are three possible
The unstacked form is a nearly square planar, extended conformation. On the other hand, the stacked conformers have two continuous double-helical domains separated by an angle of about 60° in a [[Right-hand rule|right-handed]] direction. Two of the four strands stay roughly helical, remaining within each of the two double-helical domains, while the other two cross between the two domains in an [[Antiparallel (biochemistry)|antiparallel]] fashion.<ref name="Lilley2000"/>
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The two possible stacked forms differ in which pairs of the arms are stacked with each other; which of the two dominates is highly dependent on the base sequences nearest to the junction. Some sequences result in an equilibrium between the two conformers, while others strongly prefer a single conformer. In particular, junctions containing the sequence A-CC bridging the junction point appear to strongly prefer the conformer that allows a hydrogen bond to form between the second cytosine and one of the phosphates at the junction point. While most studies have focused on the identities of the four bases nearest to the junction on each arm, it is evident that bases farther out can also affect the observed stacking conformations.<ref name="Lilley2000"/>
In junctions with symmetrical sequences, the branchpoint is mobile and can migrate in a [[random walk]] process. The rate of branch migration varies dramatically with ion concentration, with single-step times increasing from 0.
Holliday junctions with a [[Nick (DNA)|nick]], or break in one of the strands, at the junction point adopt a perpendicular orientation, and always prefer the stacking conformer that places the nick on a crossover strand rather than a helical strand.<ref name="Lilley2000"/>
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[[File:HR schematic diagram.svg|thumb|left|325px| The two pathways for [[homologous recombination]] in [[eukaryote]]s, showing the formation and resolution of Holliday junctions]]
The Holliday junction is a key intermediate in [[homologous recombination]], a biological process that increases genetic diversity by shifting genes between two [[chromosome]]s, as well as [[site-specific recombination]] events involving [[integrase]]s. They are additionally involved in [[DNA repair#Double-strand breaks|repair of double-strand breaks]].<ref name="Lilley2000"/> In addition, [[Cruciform DNA|cruciform structures]] involving Holliday junctions can arise to relieve helical strain in symmetrical sequences in [[DNA supercoil]]s.<ref>{{cite book |
The Holliday junctions in homologous recombination are between identical or nearly identical sequences, leading to a symmetric arrangement of sequences around the central junction. This allows a [[branch migration]] process to occur where the strands move through the junction point.<ref name="Lilley2000"/> Cleavage, or resolution, of the Holliday junction can occur in two ways. Cleavage of the original set of strands leads to two molecules that may show [[gene conversion]] but not [[chromosomal crossover]], while cleavage of the other set of two strands causes the resulting recombinant molecules to show crossover. All products, regardless of cleavage, are [[heteroduplex]]es in the region of Holliday junction migration.<ref name="Liu2004">{{cite journal |vauthors=Liu Y, West S | title=Happy Hollidays: 40th anniversary of the Holliday junction | journal=Nature Reviews Molecular Cell Biology | volume=5 | issue=11 | pages=937–44 | year=2004 | pmid=15520813 | doi=10.1038/nrm1502| s2cid=24520723 }}</ref>
Many proteins are able to recognize or distort the Holliday junction structure. One such class contains [[Crossover junction endodeoxyribonuclease|junction-resolving enzymes]] that cleave the junctions, sometimes in a sequence-specific fashion. Such proteins distort the structure of the junction in various ways, often pulling the junction into an unstacked conformation, breaking the central base pairs, and/or changing the angles between the four arms. Other classes are branch migration proteins that increase the exchange rate by orders of magnitude, and [[Site-specific recombination|site-specific recombinases]].<ref name="Lilley2000"/> In prokaryotes, Holliday junction resolvases fall into two families, integrases and nucleases, that are each structurally similar although their sequences are not conserved.<ref name="Liu2004"/>
In eukaryotes, two primary models for how homologous recombination repairs double-strand breaks in DNA are the double-strand break repair (DSBR) pathway (sometimes called the ''double Holliday junction model'') and the synthesis-dependent strand [[Annealing (biology)|annealing]] (SDSA) pathway.<ref name="Sung">{{Cite journal | last1=Sung |
Double-strand DNA breaks in bacteria are repaired by the [[RecBCD]] pathway of homologous recombination. Breaks that occur on only one of the two DNA strands, known as single-strand gaps, are thought to be repaired by the [[Homologous recombination#RecF pathway|RecF pathway]]. Both the RecBCD and RecF pathways include a series of reactions known as
There is evidence for recombination in some [[RNA virus]]es, specifically [[positive-sense ssRNA virus]]es like [[retrovirus]]es, [[picornavirus]]es, and [[coronavirus]]es. There is controversy over whether homologous recombination occurs in [[negative-sense ssRNA virus]]es like [[influenza]].<ref name="Boni_2010">{{cite journal | title=Guidelines for identifying homologous recombination events in influenza a virus | editor1-first=Darren P. | journal=
===Resolution===
In budding yeast ''[[Saccharomyces cerevisiae]]'', Holliday junctions can be resolved by four different pathways that account for essentially all Holliday junction resolution [[in vivo]].<ref name=Zakh>{{cite journal | last1 = Zakharyevich | first1 = K | last2 = Tang | first2 = S | last3 = Ma | first3 = Y | last4 = Hunter | first4 = N | date =
Double mutants deleted for both MLH3 (major pathway) and MMS4 (minor pathway) showed dramatically reduced crossing over compared to wild-type (6- to 17-fold); however spore viability was reasonably high (62%) and chromosomal disjunction appeared mostly functional.<ref name=Brown />
Although MUS81 is a component of a minor crossover pathway in the meiosis of budding yeast, plants and vertebrates,<ref name=Lukas>{{
The [[MSH4]] and [[MSH5]] proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans.<ref name=Pochart>{{
== Use in DNA nanotechnology ==
[[File:Mao-DX-schematic-2.svg|thumb| This double-crossover (DX) [[supramolecular complex]] contains two Holliday junctions between the two [[Double helix|double-helical]] domains, on the top and the bottom in this image. This tile is capable of forming two-dimensional arrays.<ref name="Mao04">{{cite journal | last=Mao | first=Chengde | date=December 2004 | title=The emergence of complexity: lessons from DNA | journal=
{{Main
DNA nanotechnology is the design and manufacture of artificial nucleic acid structures as engineering materials for [[nanotechnology]] rather than as the carriers of genetic information in living cells. The field uses branched DNA structures as fundamental components to create more complex, rationally designed structures. Holliday junctions are thus components of many such DNA structures. As isolated Holliday junction complexes are too flexible to assemble into large ordered arrays, [[structural motif]]s with multiple Holliday junctions are used to create rigid "[[tessellation|tiles]]" that can then assemble into larger "arrays".<ref name="Seeman-sciam">{{cite journal | last=Seeman | first=Nadrian C. | title=Nanotechnology and the double helix | journal=Scientific American | date=June 2004 | pages=64–75 | pmid=15195395
[[File:DNA tensegrity triangle.jpg|thumb|upright=1.7|left| Diagrams of a [[tensegrity]] triangle complex containing three Holliday junctions, both in isolation (a) and as part of a crystal (b, c). In addition to the two-dimensional array shown, this structure is capable of forming three-dimensional crystals.<ref>{{Cite journal|title = Lattice-free prediction of three-dimensional structure of programmed DNA assemblies
The most common such motif is the double crossover (DX) complex, which contains two Holliday junctions in close proximity to each other, resulting in a rigid structure that can self-assemble into larger arrays. The structure of the DX molecule forces the Holliday junctions to adopt a conformation with the double-helical domains directly side
The DX structural motif is the fundamental building block of the [[DNA origami]] method, which is used to make larger two- and three-dimensional structures of arbitrary shape. Instead of using individual DX tiles, a single long scaffold strand is folded into the desired shape by a number of short staple strands. When assembled, the scaffold strand is continuous through the double-helical domains, while the staple strands participate in the Holliday junctions as crossover strands.<ref>{{Cite journal | url=http://www.dna.caltech.edu/~pwkr/dna-nanotech-reviews/2012-niemeyer-DNA_origami-the_art_of_folding_DNA.pdf | title=DNA Origami: The Art of Folding DNA |
Some tile types that retain the Holliday junction's native 60° angle have been demonstrated. One such array uses tiles containing four Holliday junctions in a parallelogram arrangement. This structure had the benefit of allowing the junction angle to be directly visualized via [[atomic force microscopy]]. Tiles of three Holliday junctions in a triangular fashion have been used to make periodic three-dimensional arrays for use in [[X-ray crystallography]] of biomolecules. These structures are named for their similarity to structural units based on the principle of [[tensegrity]], which utilizes members both in tension and compression.<ref name="Seeman-sciam"/><ref name="Seeman2010"/>
== History ==
[[Robin Holliday]] proposed the junction structure that now bears his name as part of his model of homologous recombination in 1964, based on his research on the organisms ''[[Ustilago maydis]]'' and ''[[Saccharomyces cerevisiae]].'' The model provided a molecular mechanism that explained both [[gene conversion]] and [[chromosomal crossover]]. Holliday realized that the proposed pathway would create [[heteroduplex | heteroduplex DNA segments]] with base mismatches between different versions of a single gene. He predicted that the cell would have a mechanism for mismatch repair, which was later discovered.<ref name="Liu2004"/> Prior to Holliday's model, the accepted model involved a [[copy-choice mechanism]]<ref name="Stahl">{{cite journal | author=Stahl FW | title=The Holliday junction on its thirtieth anniversary | journal=Genetics | volume=138 | issue=2 | date=1 October 1994 | pages=241–246 | doi=10.1093/genetics/138.2.241 | format=[[PDF]] | url=http://www.genetics.org/cgi/reprint/138/2/241 | pmid=7828807 | pmc=1206142 }}</ref> where the new strand is synthesized directly from parts of the different parent strands.<ref>{{Cite book | title=Advances in genetics | url=https://books.google.com/books?id=TUn8spJIG3UC&pg=PA16 | publisher=Academic Press | date=1971 | isbn=9780080568027 }}</ref>
In the original Holliday model for homologous recombination, single-strand breaks occur at the same point on one strand of each parental DNA. Free ends of each broken strand then migrate across to the other DNA helix. There, the invading strands are joined to the free ends they encounter, resulting in the Holliday junction. As each crossover strand reanneals to its original partner strand, it displaces the original complementary strand ahead of it. This causes the Holliday junction to migrate, creating the heteroduplex segments. Depending on which strand was used as a template to repair the other, the four cells resulting from [[meiosis]] might end up with three copies of one allele and only one of the other, instead of the normal two of each, a property known as gene conversion.<ref name="Liu2004"/>
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Holliday's original model assumed that heteroduplex DNA would be present on both chromosomes, but experimental data on yeast refuted this. An updated model by [[Matthew Meselson|Matt Meselson]] and [[Charley Radding]] in 1975 introduced the idea of branch migration.<ref name="Stahl"/> Further observations in the 1980s led to the proposal of alternate mechanisms for recombination such as the double-strand break model (by [[Jack Szostak]], [[Frank Stahl]], and others) and the single-strand annealing model. A third, the synthesis-dependent strand annealing model, did not involve Holliday junctions.<ref name="Liu2004"/>
The first experimental evidence for the structure of the Holliday junction came from [[electron microscopy]] studies in the late 1970s, where the four-arm structure was clearly visible in images of [[plasmid]] and [[bacteriophage]] DNA. Later in the 1980s, enzymes responsible for initiating the formation of, and binding to, Holliday junctions were identified, although as of 2004 the identification of mammalian Holliday junction resolvases remained elusive (however, see section "Resolution of Holliday junctions," above for more recent information). In 1983, artificial Holliday junction molecules were first constructed from synthetic [[oligonucleotide]]s by [[Nadrian Seeman]], allowing for more direct study of their physical properties. Much of the early analysis of Holliday junction structure was inferred from [[gel electrophoresis]], [[Förster resonance energy transfer|FRET]], and [[hydroxyl radical]] and [[nuclease]] footprinting studies. In the 1990s, [[crystallography]] and [[Nuclear magnetic resonance spectroscopy of nucleic acids|nucleic acid NMR]] methods became available, as well as computational [[molecular modelling]] tools.<ref name="Lilley2000"/><ref name="Liu2004"/><ref name="Hays2003">{{cite journal | title=Caution! DNA Crossing: Crystal Structures of Holliday Junctions |vauthors=Hays FA, Watson J, Ho PS | journal=J Biol Chem | volume=278 | issue=50 | pages=49663–49666 | year=2003 | doi=10.1074/jbc.R300033200 | pmid=14563836| doi-access=free }}</ref>
Initially, geneticists assumed that the junction would adopt a parallel rather than [[Antiparallel (biochemistry)|antiparallel]] conformation, because that would place the homologous duplexes in closer alignment to each other.<ref name="Lilley2000"/> Chemical analysis in the 1980s showed that the junction actually preferred the antiparallel conformation, a finding that was considered controversial, and Robin Holliday himself initially doubted the findings.<ref name="Lilley2000"/><ref name="Liu2004"/> The antiparallel structure later became widely accepted due to X-ray crystallography data on ''in vitro'' molecules, although as of 2004 the implications for the ''in vivo'' structure remained unclear, especially the structure of the junctions is often altered by proteins bound to it.<ref name="Liu2004"/>
The conceptual foundation for DNA nanotechnology was first laid out by [[Nadrian Seeman]] in the early 1980s.<ref name="Pelesko">{{cite book |last = Pelesko|first = John A.|title = Self-assembly: the science of things that put themselves together|year = 2007|publisher = Chapman & Hall/CRC|location = New York|isbn = 978-1-58488-687-7|pages = 201, 242, 259}}</ref> A number of natural branched DNA structures were known at the time, including the DNA [[replication fork]] and the mobile Holliday junction, but Seeman's insight was that immobile nucleic acid junctions could be created by properly designing the strand sequences to remove symmetry in the assembled molecule, and that these immobile junctions could in principle be combined into rigid crystalline lattices. The first theoretical paper proposing this scheme was published in 1982, and the first experimental demonstration of an immobile DNA junction was published the following year.<ref name="Seeman2010"/><ref name="ShihYanChallenges">{{Cite journal | last1 = Pinheiro | first1 = A. V. | last2 = Han | first2 = D. | last3 = Shih | first3 = W. M. | last4 = Yan | first4 = H. | title = Challenges and opportunities for structural DNA nanotechnology | journal = Nature Nanotechnology | volume = 6 | issue = 12 | pages = 763–772 | date=December 2011 | pmid = 22056726 | pmc = 3334823 | doi = 10.1038/nnano.2011.187| bibcode = 2011NatNa...6..763P }}</ref> Seeman developed the more rigid double-crossover (DX) [[Structural motif|motif]], suitable for forming two-dimensional lattices, demonstrated in 1998 by him and [[Erik Winfree]].<ref name="Seeman-sciam"/> In 2006, [[Paul Rothemund]] first demonstrated the [[DNA origami]] technique for easily and robustly creating folded DNA structures of arbitrary shape. This method allowed the creation of much larger structures than were previously possible, and which are less technically demanding to design and synthesize.<ref name="origamichapter">{{cite book |doi = 10.1007/3-540-30296-4_1|editor1-first = Junghuei|editor1-last = Chen|editor2-first = Natasha|editor2-last = Jonoska|editor3-first = Grzegorz|editor3-last = Rozenberg|title = Nanotechnology: science and computation|url = https://archive.org/details/nanotechnologysc00chen_376|url-access = limited|series = Natural Computing Series|year = 2006|publisher = Springer|location = New York|isbn = 978-3-540-30295-7|first = Paul W. K.|last = Rothemund|chapter = Scaffolded DNA origami: from generalized multicrossovers to polygonal networks|pages = 3–21}}</ref> The synthesis of a three-dimensional lattice was finally published by Seeman in 2009, nearly thirty years after he had set out to achieve it.<ref name="growsup">{{cite journal|last = Service|first = Robert F.|title = DNA nanotechnology grows up|journal = Science|date = 3 June 2011|volume = 332|pages = 1140–1143|doi = 10.1126/science.332.6034.1140|issue = 6034|pmid=21636754|bibcode = 2011Sci...332.1140S}}</ref>
==References==
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*{{MeshName | Holliday+junctions}}
*[http://www.ks.uiuc.edu/Research/H-Junction/ Conformational Change of Holliday Junction]
*[https://web.archive.org/web/20061116000946/http://www.natureprotocols.com/2006/09/01/analysis_of_branch_migration_a.php Analysis of branch migration activities of proteins using synthetic DNA substrates (a protocol)]
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