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in the resolution phase of recombination any holliday junctions formed by the strand invasion process are cut thereby restoring two separate dna molecules this cleavage is done by <unk> complex interacting with ruvc which together form the ruvabc complex ruvc is an endonuclease that cuts the degenerate sequence 5 ' ( a / t ) tt ( g / c ) 3 ' the sequence is found frequently in dna about once every 64 nucleotides before cutting ruvc likely gains access to the holliday junction by displacing one of the two ruva tetramers covering the dna there recombination results in either splice or patch products depending on how ruvc cleaves the holliday junction splice products are crossover products in which there is a rearrangement of genetic material around the site of recombination patch products on the other hand are non @@ crossover products in which there is no such rearrangement and there is only a patch of hybrid dna in the recombination product
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= = = facilitating genetic transfer = = =
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homologous recombination is an important method of integrating donor dna into a recipient organism 's genome in horizontal gene transfer the process by which an organism incorporates foreign dna from another organism without being the offspring of that organism homologous recombination requires incoming dna to be highly similar to the recipient genome and so horizontal gene transfer is usually limited to similar bacteria studies in several species of bacteria have established that there is a log @@ linear decrease in recombination frequency with increasing difference in sequence between host and recipient dna
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in bacterial conjugation where dna is transferred between bacteria through direct cell @@ to @@ cell contact homologous recombination helps integrate foreign dna into the host genome via the recbcd pathway the recbcd enzyme promotes recombination after dna is converted from single @@ strand dna in which form it originally enters the bacterium to double @@ strand dna during replication the recbcd pathway is also essential for the final phase of transduction a type of horizontal gene transfer in which dna is transferred from one bacterium to another by a virus foreign bacterial dna is sometimes <unk> in the capsid head of bacteriophage virus particles as dna is packaged into new bacteriophages during viral replication when these new bacteriophages infect other bacteria dna from the previous host bacterium is injected into the new bacterial host as double @@ strand dna the recbcd enzyme then incorporates this double @@ strand dna into the genome of the new bacterial host
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= = = bacterial transformation = = =
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natural bacterial transformation involves the transfer of dna from a donor bacterium to a recipient bacterium where both donor and recipient are ordinarily of the same species transformation unlike bacterial conjugation and transduction depends on numerous bacterial gene products that specifically interact to perform this process thus transformation is clearly a bacterial adaptation for dna transfer in order for a bacterium to bind take up and integrate donor dna into its resident chromosome by homologous recombination it must first enter a special physiological state termed competence the reca / rad51 / dmc1 gene family plays a central role in homologous recombination during bacterial transformation as it does during eukaryotic meiosis and mitosis for instance the reca protein is essential for transformation in bacillus subtilis and streptococcus pneumoniae and expression of the reca gene is induced during the development of competence for transformation in these organisms
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as part of the transformation process the reca protein interacts with entering single @@ stranded dna ( ssdna ) to form reca / ssdna <unk> that scan the resident chromosome for regions of homology and bring the entering ssdna to the corresponding region where strand exchange and homologous recombination occur thus the process of homologous recombination during bacterial transformation has fundamental similarities to homologous recombination during meiosis
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= = in viruses = =
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homologous recombination occurs in several groups of viruses in dna viruses such as herpesvirus recombination occurs through a break @@ and @@ rejoin mechanism like in bacteria and eukaryotes there is also evidence for recombination in some rna viruses specifically positive @@ sense ssrna viruses like retroviruses picornaviruses and coronaviruses there is controversy over whether homologous recombination occurs in negative @@ sense ssrna viruses like influenza
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in rna viruses homologous recombination can be either precise or imprecise in the precise type of rna @@ rna recombination there is no difference between the two parental rna sequences and the resulting crossover rna region because of this it is often difficult to determine the location of crossover events between two recombining rna sequences in imprecise rna homologous recombination the crossover region has some difference with the parental rna sequences caused by either addition deletion or other modification of nucleotides the level of precision in crossover is controlled by the sequence context of the two recombining strands of rna sequences rich in adenine and uracil decrease crossover precision
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homologous recombination is important in facilitating viral evolution for example if the genomes of two viruses with different disadvantageous mutations undergo recombination then they may be able to regenerate a fully functional genome alternatively if two similar viruses have infected the same host cell homologous recombination can allow those two viruses to swap genes and thereby evolve more potent variations of themselves
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homologous recombination is the proposed mechanism whereby the dna virus human herpesvirus @@ 6 integrates into human telomeres
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when two or more viruses each containing lethal genomic damage infect the same host cell the virus genomes can often pair with each other and undergo homologous recombinational repair to produce viable progeny this process known as multiplicity reactivation has been studied in several bacteriophages including phage t4 enzymes employed in recombinational repair in phage t4 are functionally homologous to enzymes employed in bacterial and eukaryotic recombinational repair in particular with regard to a gene necessary for the strand exchange reaction a key step in homologous recombinational repair there is functional homology from viruses to humans ( i e <unk> in phage t4 reca in e coli and other bacteria and <unk> and <unk> in yeast and other eukaryotes including humans ) multiplicity reactivation has also been demonstrated in numerous pathogenic viruses
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= = effects of dysfunction = =
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without proper homologous recombination chromosomes often incorrectly align for the first phase of cell division in meiosis this causes chromosomes to fail to properly segregate in a process called <unk> in turn <unk> can cause sperm and ova to have too few or too many chromosomes down 's syndrome which is caused by an extra copy of chromosome 21 is one of many abnormalities that result from such a failure of homologous recombination in meiosis
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deficiencies in homologous recombination have been strongly linked to cancer formation in humans for example each of the cancer @@ related diseases bloom 's syndrome werner 's syndrome and <unk> @@ thomson syndrome are caused by malfunctioning copies of <unk> helicase genes involved in the regulation of homologous recombination blm wrn and <unk> respectively in the cells of bloom 's syndrome patients who lack a working copy of the blm protein there is an elevated rate of homologous recombination experiments in mice deficient in blm have suggested that the mutation gives rise to cancer through a loss of heterozygosity caused by increased homologous recombination a loss in heterozygosity refers to the loss of one of two versions or alleles of a gene if one of the lost alleles helps to suppress tumors like the gene for the <unk> protein for example then the loss of heterozygosity can lead to cancer
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decreased rates of homologous recombination cause inefficient dna repair which can also lead to cancer this is the case with brca1 and brca2 two similar tumor suppressor genes whose malfunctioning has been linked with considerably increased risk for breast and ovarian cancer cells missing brca1 and brca2 have a decreased rate of homologous recombination and increased sensitivity to ionizing radiation suggesting that decreased homologous recombination leads to increased susceptibility to cancer because the only known function of brca2 is to help initiate homologous recombination researchers have speculated that more detailed knowledge of brca2 's role in homologous recombination may be the key to understanding the causes of breast and ovarian cancer
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= = evolutionary conservation = =
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while the pathways can mechanistically vary the ability of organisms to perform homologous recombination is universally conserved across all domains of life based on the similarity of their amino acid sequences homologs of a number of proteins can be found in multiple domains of life indicating that they evolved a long time ago and have since diverged from common ancestral proteins
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reca recombinase family members are found in almost all organisms with reca in bacteria rad51 and dmc1 in eukaryotes rada in archaea and <unk> in t4 phage
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related single stranded binding proteins that are important for homologous recombination and many other processes are also found in all domains of life
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<unk> <unk> <unk> and a number of other proteins are also found in both archaea and eukaryotes
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= = = the reca <unk> family = = =
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the proteins of the reca recombinase family of proteins are thought to be descended from a common ancestral recombinase the reca recombinase family contains reca protein from bacteria the rad51 and dmc1 proteins from eukaryotes and rada from archaea and the recombinase <unk> proteins studies modeling the evolutionary relationships between the rad51 dmc1 and rada proteins indicate that they are monophyletic or that they share a common molecular ancestor within this protein family rad51 and dmc1 are grouped together in a separate clade from rada one of the reasons for grouping these three proteins together is that they all possess a modified helix @@ turn @@ helix motif which helps the proteins bind to dna toward their n @@ terminal ends an ancient gene duplication event of a eukaryotic reca gene and subsequent mutation has been proposed as a likely origin of the modern rad51 and dmc1 genes
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the proteins generally share a long conserved region known as the reca / rad51 domain within this protein domain are two sequence motifs walker a motif and walker b motif the walker a and b motifs allow members of the reca / rad51 protein family to engage in atp binding and atp hydrolysis
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= = = <unk> specific proteins = = =
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the discovery of dmc1 in several species of giardia one of the earliest protists to diverge as a eukaryote suggests that meiotic homologous recombination and thus meiosis itself emerged very early in eukaryotic evolution in addition to research on dmc1 studies on the spo11 protein have provided information on the origins of meiotic recombination spo11 a type ii topoisomerase can initiate homologous recombination in meiosis by making targeted double @@ strand breaks in dna phylogenetic trees based on the sequence of genes similar to <unk> in animals fungi plants protists and archaea have led scientists to believe that the version spo11 currently in eukaryotes emerged in the last common ancestor of eukaryotes and archaea
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= = technological applications = =
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= = = gene targeting = = =
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many methods for introducing dna sequences into organisms to create recombinant dna and genetically modified organisms use the process of homologous recombination also called gene targeting the method is especially common in yeast and mouse genetics the gene targeting method in knockout mice uses mouse embryonic stem cells to deliver artificial genetic material ( mostly of therapeutic interest ) which represses the target gene of the mouse by the principle of homologous recombination the mouse thereby acts as a working model to understand the effects of a specific mammalian gene in recognition of their discovery of how homologous recombination can be used to introduce genetic modifications in mice through embryonic stem cells mario capecchi martin evans and oliver smithies were awarded the 2007 nobel prize for physiology or medicine
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advances in gene targeting technologies which hijack the homologous recombination mechanics of cells are now leading to the development of a new wave of more accurate <unk> human disease models these engineered human cell models are thought to more accurately reflect the genetics of human diseases than their mouse model predecessors this is largely because mutations of interest are introduced into endogenous genes just as they occur in the real patients and because they are based on human genomes rather than rat genomes furthermore certain technologies enable the knock @@ in of a particular mutation rather than just knock @@ outs associated with older gene targeting technologies
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= = = protein engineering = = =
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protein engineering with homologous recombination develops chimeric proteins by swapping fragments between two parental proteins these techniques exploit the fact that recombination can introduce a high degree of sequence diversity while preserving a protein 's ability to fold into its tertiary structure or three @@ dimensional shape this stands in contrast to other protein engineering techniques like random point mutagenesis in which the probability of maintaining protein function declines exponentially with increasing amino acid substitutions the chimeras produced by recombination techniques are able to maintain their ability to fold because their swapped parental fragments are structurally and evolutionarily conserved these <unk> building blocks preserve structurally important interactions like points of physical contact between different amino acids in the protein 's structure computational methods like <unk> and statistical coupling analysis can be used to identify structural subunits suitable for recombination
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techniques that rely on homologous recombination have been used to engineer new proteins in a study published in 2007 researchers were able to create chimeras of two enzymes involved in the biosynthesis of isoprenoids a diverse class of compounds including hormones visual pigments and certain pheromones the chimeric proteins acquired an ability to catalyze an essential reaction in isoprenoid biosynthesis one of the most diverse pathways of biosynthesis found in nature that was absent in the parent proteins protein engineering through recombination has also produced chimeric enzymes with new function in members of a group of proteins known as the cytochrome p450 family which in humans is involved in detoxifying foreign compounds like drugs food additives and preservatives
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= = = cancer therapy = = =
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cancer cells with brca mutations have deficiencies in homologous recombination and drugs to exploit those deficiencies have been developed and used successfully in clinical trials <unk> a parp1 inhibitor shrunk or stopped the growth of tumors from breast ovarian and prostate cancers caused by mutations in the brca1 or brca2 genes which are necessary for hr when brca1 or brca2 is absent other types of dna repair mechanisms must compensate for the deficiency of hr such as base @@ excision repair ( ber ) for stalled replication forks or non @@ homologous end joining ( nhej ) for double strand breaks by inhibiting ber in an hr @@ deficient cell <unk> applies the concept of synthetic lethality to specifically target cancer cells while parp1 inhibitors represent a novel approach to cancer therapy researchers have cautioned that they may prove insufficient for treating late @@ stage metastatic cancers cancer cells can become resistant to a parp1 inhibitor if they undergo deletions of mutations in brca2 undermining the drug 's synthetic lethality by restoring cancer cells ' ability to repair dna by hr
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= ronnie mann =
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ronnie mann ( born 12 october 1986 ) is an english professional mixed martial artist who competes in the featherweight division a professional mma competitor since 2003 mann has mostly fought in england and japan
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mann is a veteran of the former top english organisation cage rage championships and was a quarter @@ finalist in the sengoku featherweight grand prix in 2009 losing to hatsu hioki mann is also the current shark fights featherweight champion after defeating doug evans in september 2010
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= = mixed martial arts career = =
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= = = background and early career = = =
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mann grew up in cheltenham england mann also idolised marco <unk> and royce gracie as a youngster after being introduced to the ultimate fighting championship mann began taking muay thai lessons at the age of 11 and participated in jiu @@ jitsu and kickboxing tournaments at the age of 13 mann competed in his first amateur fight at the age of 16 and turned professional a year later in japan he fought under the name of ronnie ushiwaka his mother 's maiden name ( his mothers maiden name was <unk> ( <unk> ) mann 's professional mixed martial arts career began in november 2003 with a win over andy dicks a few months later mann made his shooto debut at shooto holland where he won via triangle choke after 56 seconds staying in holland mann won a further fight knocking his opponent out in under two minutes mann then recorded five successive submission victories
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= = = domestic prominence = = =
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in mid @@ 2006 mann signed with top domestic organisation cage rage and made his promotional debut at the cage rage contenders 1 event against ashleigh grimshaw mann later stated that the fight was one of his toughest especially after being hit with an early low blow the organisation at the time adopted the open guard rule allowing fighters to stomp on each other at the end of the third round the fight was declared a draw despite mann feeling that he had the better of the fight after a knockdown in the first round and a triangle choke attempt in the second round
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mann later joined the cage gladiators promotion in england and made his promotional debut at cage gladiators 2 against <unk> <unk> winning via submission ( strikes ) at 1 42 of the first round three months later mann returned at cage gladiators 3 defeating chris freeborn via submission ( triangle choke ) at 2 46 of the first round
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at cage rage 20 in a rematch with ashleigh grimshaw whom mann had earlier drawn with mann controlled the stand @@ up and the top position on the floor towards the end of the fight grimshaw attempted a comeback utilising ground @@ and @@ pound offense though mann was declared the winner via unanimous decision after three rounds
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mann 's next fight ( and third in the cage rage organisation ) was against top domestic prospect robbie olivier the fight saw both fighters neutralise the other 's ground game in the stand @@ up mann was regarded as being unusually tentative which gave olivier the opportunity to take him to the floor where again neither fighter was able to advance position or do anything of note after three rounds olivier was declared the winner via unanimous decision
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at cage rage 24 mann faced jordan miller who took the fight at short notice mann was able to take miller down almost immediately in the fight and took a rear naked choke mann dominated from that point and soon after transitioned to a triangle choke after just 53 seconds of the first round
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after this cage rage became defunct and mann re @@ joined cage gladiators immediately competing against frederic fernandez for the cage gladiators world featherweight championship at the cage gladiators 6 event mann was able to utilise his wrestling skills again dominating the takedowns neutralising his opponent mann was able to take the unanimous decision after effective striking leading sherdog to once again label him a star in the making
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mann was then scheduled to face future world extreme cagefighting standout brad pickett though the fight was later cancelled after pickett suffered a broken arm defending a high kick
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mann instead took a fight in croatia defeating ivica <unk> via tko ( injury ) returning to cage gladiators at the cage gladiators 8 event mann defeated steve mccombe via submission ( choke ) in the first round
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= = = sengoku = = =
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mann then signed with sengoku raiden championship in japan to participate in their featherweight grand prix in the opening round mann faced tetsuya yamada and defeated him via unanimous decision ( 30 29 30 29 30 29 ) during the first round of the fight mann was able to land powerful punches before falling into a deep <unk> attempt from yamada after escaping mann was able to gain top position to end the first round the second round saw yamada attempt a standing kimura which was fought off by mann who was later able to take down yamada twice whilst fighting off a second kimura attempt the final round saw poor kickboxing attempts by yamada which was countered by two takedowns finally mann looked to utilise an ankle lock which was reversed into another <unk> by yamada after the third round ended mann was declared the winner via decision
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in the quarter finals of the tournament mann faced early tournament favourite hatsu hioki who had previously defeated world extreme cagefighting veteran chris manuel mann weighed in at 142 @@ 6 lbs whilst hioki who was unbeaten in his last seven fights weighed in at 143 @@ 3 lbs mann stated that [ i ] plan for an exciting and explosive fight
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during the fight mann was able to land several successful punches before hioki took mann down with a trip where he was able to land knees and execute a d <unk> choke after scrambling to avoid an armbar attempt mann fell to a triangle choke tapping out at 3 09 of the first round after the fight mann stated i started off well standing up but i fell into his game fell into his trap the punches were only small punches but it was the triangle that was slowly coming on so in the end i tapped
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after his elimination from the featherweight grand prix mann competed in his third fight in sengoku against shigeki osawa who sherdog labelled a talented young prospect after three rounds mann was victorious via unanimous decision
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= = = move to north america = = =
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mann still had one more fight left on his sengoku contract and also expressed a desire to join world extreme cagefighting and eventually fight featherweight champion jose aldo
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despite his contract with sengoku mann went on to make his north american debut against doug evans on 11 september 2010 at shark fights 13 the bout saw mann hit evans with multiple combinations and low kicks before utilising a flying knee evans counter @@ attacked with takedowns which he kept up into the final round mann won the bout via split decision ( 47 48 48 47 48 47 ) to become the new shark fights featherweight champion
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= = = bellator fighting championships = = =
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on 17 february it was announced mann had signed with bellator fighting championships he had his first fight for the promotion against josh <unk> at bellator 42 mann was able to dominate the fight with superior wrestling and won the fight via unanimous decision ( 30 @@ 25 30 @@ 27 30 @@ 27 )
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that win earned mann a place in the bellator 2011 summer series featherweight tournament where he faced adam schindler at bellator 46 in his quarter final match @@ up mann stuffed all attempts from the wrestler to take the fight to the ground before he scored a stunning first round ko win with a right uppercut left hook combination which dropped schindler before swarming on him with <unk> to leave him unconscious on the mat
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