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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 .
= = = Facilitating genetic transfer = = =
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 .
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 .
= = = Bacterial transformation = = =
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 .
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 .
= = In viruses = =
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 .
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 .
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 .
Homologous recombination is the proposed mechanism whereby the DNA virus human herpesvirus @-@ 6 integrates into human telomeres .
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 .
= = Effects of dysfunction = =
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 .
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 .
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 .
= = Evolutionary Conservation = =
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 .
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 .
Related single stranded binding proteins that are important for homologous recombination , and many other processes , are also found in all domains of life .
<unk> , <unk> , <unk> , and a number of other proteins are also found in both archaea and eukaryotes .
= = = The RecA <unk> Family = = =
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 .
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 .
= = = <unk> specific proteins = = =
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 .
= = Technological applications = =
= = = Gene targeting = = =
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 .
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 .
= = = Protein engineering = = =
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 .
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 .
= = = Cancer therapy = = =
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 .
= Ronnie Mann =
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 .
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 .
= = Mixed martial arts career = =
= = = Background and early career = = =
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 .
= = = Domestic prominence = = =
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 .
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 .
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 .
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 .
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 .
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 . "
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 .
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 .
= = = Sengoku = = =
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 .
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 . "
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 . "
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 .
= = = Move to North America = = =
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 .
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 .
= = = Bellator Fighting Championships = = =
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 ) .
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 .