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60-458: In prokaryotes RecQ is necessary for plasmid recombination and DNA repair from UV-light, free radicals, and alkylating agents. This protein can also reverse damage from replication errors. In eukaryotes, replication does not proceed normally in the absence of RecQ proteins, which also function in aging, silencing, recombination and DNA repair. RecQ family members share three regions of conserved protein sequence referred to as the: The removal of

120-612: A 3’ to 5’ exonuclease subunit, one of the three separately encoded core proteins of the DNA polymerase III holoenzyme. In contrast to E. coli and S. typhimurium , where the polymerase and editing functions are encoded by separate genes, in the bacterial species Buchnera aphidicola the DNA polymerase encoded by the DNA III (polC) gene contains both DNA polymerase and 3’ to 5’ exonuclease domains. An evolutionary divergence (about 0.25 to 1.2 billion years ago), appears to have been associated with

180-477: A 5' exonuclease (human gene Xrn2) to degrade the newly formed transcript downstream, leaving the polyadenylation site and simultaneously shooting the polymerase. This process involves the exonuclease's catching up to the pol II and terminating the transcription. Pol I then synthesizes DNA nucleotides in place of the RNA primer it had just removed. DNA polymerase I also has 3' to 5' and 5' to 3' exonuclease activity, which

240-519: A benefit to pathogenic bacteria by allowing repair of DNA damage, particularly damages that occur in the inflammatory, oxidizing environment associated with infection of a host. When two or more viruses, each containing lethal genomic damages, infect the same host cell, the virus genomes can often pair with each other and undergo HRR to produce viable progeny. This process, referred to as multiplicity reactivation, has been studied in lambda and T4 bacteriophages , as well as in several pathogenic viruses. In

300-449: A chromosome if they know the frequency of the crossovers. Geneticists can also use this method to infer the presence of certain genes. Genes that typically stay together during recombination are said to be linked . One gene in a linked pair can sometimes be used as a marker to deduce the presence of the other gene. This is typically used to detect the presence of a disease-causing gene. The recombination frequency between two loci observed

360-422: A complex with RAD51 , RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair. Evidence was presented that WRN plays a direct role in the repair of methylation induced DNA damage . The process likely involves the helicase and exonuclease activities of WRN that operate together with DNA polymerase beta in long patch base excision repair . WRN

420-432: A form of recombination. Recombination also occurs in the reoviridae (dsRNA)(e.g. reovirus), orthomyxoviridae ((-)ssRNA)(e.g. influenza virus ) and coronaviridae ((+)ssRNA) (e.g. SARS ). Recombination in RNA viruses appears to be an adaptation for coping with genome damage. Switching between template strands during genome replication, referred to as copy-choice recombination, was originally proposed to explain

480-426: A high level of somatic recombination. The proper function of RecQ helicases requires the specific interaction with topoisomerase III (Top 3). Top 3 changes the topological status of DNA by binding and cleaving single stranded DNA and passing either a single stranded or a double stranded DNA segment through the transient break and finally re-ligating the break. The interaction of RecQ helicase with topoisomerase III at

540-965: A predisposition to cancer. There are at least five human RecQ genes; and mutations in three human RecQ genes are implicated in heritable human diseases: WRN gene in Werner syndrome (WS), BLM gene in Bloom syndrome (BS), and RECQL4 in Rothmund–Thomson syndrome . These syndromes are characterized by premature aging, and can give rise to the diseases of cancer , type 2 diabetes , osteoporosis , and atherosclerosis , which are commonly found in old age. These diseases are associated with high incidence of chromosomal abnormalities, including chromosome breaks, complex rearrangements, deletions and translocations, site specific mutations , and in particular sister chromatid exchanges (more common in BS) that are believed to be caused by

600-525: A process called synthesis-dependent strand annealing (SDSA) (see Misplaced Pages article " Genetic recombination "). It is estimated that only about 5% of double-strand breaks are repaired by crossover recombination. Sequela-Arnaud et al. suggested that crossover numbers are restricted because of the long-term costs of crossover recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection . In humans, individuals with Rothmund–Thomson syndrome , and carrying

660-489: A role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ). WRN also physically interacts with the major NHEJ factor X4L4 ( XRCC4 - DNA ligase 4 complex). X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4. WRN also appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks. WRN participates in

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720-410: A specific type of function or requirement. Exonuclease I breaks apart single-stranded DNA in a 3' → 5' direction, releasing deoxyribonucleoside 5'-monophosphates one after another. It does not cleave DNA strands without terminal 3'-OH groups because they are blocked by phosphoryl or acetyl groups. Exonuclease II is associated with DNA polymerase I, which contains a 5' exonuclease that clips off

780-424: A time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is the endonuclease , which cleaves phosphodiester bonds in the middle (endo) of a polynucleotide chain. Eukaryotes and prokaryotes have three types of exonucleases involved in the normal turnover of mRNA : 5′ to 3′ exonuclease (Xrn1) , which

840-542: A variety of exogenous agents (e.g. UV light , X-rays , chemical cross-linking agents) can be repaired by homologous recombinational repair (HRR). These findings suggest that DNA damages arising from natural processes , such as exposure to reactive oxygen species that are byproducts of normal metabolism, are also repaired by HRR. In humans, deficiencies in the gene products necessary for HRR during meiosis likely cause infertility In humans, deficiencies in gene products necessary for HRR, such as BRCA1 and BRCA2 , increase

900-401: Is a 3' to 5' hydrolyzing enzyme that catalyzes linear double-stranded DNA and single-stranded DNA, which requires Ca2+ . This enzyme is extremely important in the process of homologous recombination . Exonuclease VIII is 5' to 3' dimeric protein that does not require ATP or any gaps or nicks in the strand, but requires a free 5' OH group to carry out its function . In Escherichia coli

960-571: Is a common mechanism used in DNA repair . Gene conversion – the process during which homologous sequences are made identical also falls under genetic recombination. Genetic recombination and recombinational DNA repair also occurs in bacteria and archaea , which use asexual reproduction . Recombination can be artificially induced in laboratory ( in vitro ) settings, producing recombinant DNA for purposes including vaccine development. V(D)J recombination in organisms with an adaptive immune system

1020-411: Is a dependent decapping protein ; 3′ to 5′ exonuclease, an independent protein; and poly(A)-specific 3′ to 5′ exonuclease. In both archaea and eukaryotes , one of the main routes of RNA degradation is performed by the multi-protein exosome complex , which consists largely of 3′ to 5′ exoribonucleases . RNA polymerase II is known to be in effect during transcriptional termination; it works with

1080-502: Is a general transcription regulatory complex in budding yeast that is found to be associated with mRNA metabolism, transcription initiation, and mRNA degradation. CCR4 has been found to contain RNA and single-stranded DNA 3' to 5' exonuclease activities. Another component associated with the CCR4-Not is CAF1 protein, which has been found to contain 3' to 5' or 5' to 3' exonuclease domains in

1140-596: Is a small probability of recombination at any location along a chromosome, the frequency of recombination between two locations depends on the distance separating them. Therefore, for genes sufficiently distant on the same chromosome, the amount of crossover is high enough to destroy the correlation between alleles. Tracking the movement of genes resulting from crossovers has proven quite useful to geneticists. Because two genes that are close together are less likely to become separated than genes that are farther apart, geneticists can deduce roughly how far apart two genes are on

1200-411: Is a type of site-specific genetic recombination that helps immune cells rapidly diversify to recognize and adapt to new pathogens . During meiosis, synapsis (the pairing of homologous chromosomes) ordinarily precedes genetic recombination. Genetic recombination is catalyzed by many different enzymes . Recombinases are key enzymes that catalyse the strand transfer step during recombination. RecA ,

1260-461: Is altered. Gene conversion has often been studied in fungal crosses where the 4 products of individual meioses can be conveniently observed. Gene conversion events can be distinguished as deviations in an individual meiosis from the normal 2:2 segregation pattern (e.g. a 3:1 pattern). Recombination can occur between DNA sequences that contain no sequence homology . This can cause chromosomal translocations , sometimes leading to cancer. B cells of

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1320-555: Is called recombinant DNA . A prime example of such a use of genetic recombination is gene targeting , which can be used to add, delete or otherwise change an organism's genes. This technique is important to biomedical researchers as it allows them to study the effects of specific genes. Techniques based on genetic recombination are also applied in protein engineering to develop new proteins of biological interest. Examples include Restriction enzyme mediated integration , Gibson assembly and Golden Gate Cloning . DNA damages caused by

1380-479: Is depleted, HR-mediated repair and 5' end resection are severely reduced in vivo . RECQL4 also appears to be necessary for other forms of DNA repair including non-homologous end joining , nucleotide excision repair and base excision repair . The association of deficient RECQL4 mediated DNA repair with accelerated aging is consistent with the DNA damage theory of aging . Genetic recombination Genetic recombination (also known as genetic reshuffling )

1440-667: Is exemplified by the diseases that arise as a consequence of mutations or malfunctions in RecQ helicases; thus it is crucial that RecQ is present and functional to ensure proper human growth and development. The Werner syndrome ATP-dependent helicase (WRN helicase) is unusual among RecQ DNA family helicases in having an additional exonuclease activity. WRN interacts with DNA-PKcs and the Ku protein complex. This observation, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests

1500-406: Is the crossing-over value . It is the frequency of crossing over between two linked gene loci ( markers ), and depends on the distance between the genetic loci observed. For any fixed set of genetic and environmental conditions, recombination in a particular region of a linkage structure ( chromosome ) tends to be constant, and the same is then true for the crossing-over value which is used in

1560-785: Is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes , genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) int er chromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes (random orientation of pairs of homologous chromosomes in meiosis I); & (2) int ra chromosomal recombination, occurring through crossing over. During meiosis in eukaryotes , genetic recombination involves

1620-408: Is used in editing and proofreading DNA for errors. The 3' to 5' can only remove one mononucleotide at a time, and the 5' to 3' activity can remove mononucleotides or up to 10 nucleotides at a time. In 1971, Lehman IR discovered exonuclease I in E. coli . Since that time, there have been numerous discoveries including: exonuclease, II, III , IV, V , VI, VII , and VIII. Each type of exonuclease has

1680-601: Is well documented in male Drosophila melanogaster . The "Haldane-Huxley rule" states that achiasmy usually occurs in the heterogametic sex . Heterochiasmy occurs when recombination rates differ between the sexes of a species. In humans, each oocyte has on average 41.6 ± 11.3 recombinations, 1.63-fold higher than sperms. This sexual dimorphic pattern in recombination rate has been observed in many species. In mammals, females most often have higher rates of recombination. Numerous RNA viruses are capable of genetic recombination when at least two viral genomes are present in

1740-859: The Diamond Princess cruise, two mutations, 29736G > T and 29751G > T (G13 and G28) were located in Coronavirus 3′ stem-loop II-like motif (s2m) of SARS-CoV-2. Although s2m is considered an RNA motif highly conserved in 3' untranslated region among many coronavirus species, this result also suggests that s2m of SARS-CoV-2 is RNA recombination /mutation hotspot. SARS-CoV-2's entire receptor binding motif appeared, based on preliminary observations, to have been introduced through recombination from coronaviruses of pangolins . However, more comprehensive analyses later refuted this suggestion and showed that SARS-CoV-2 likely evolved solely within bats and with little or no recombination. Nowak and Ohtsuki noted that

1800-506: The RECQL4 germline mutation , have several clinical features of accelerated aging . These features include atrophic skin and pigment changes, alopecia , osteopenia , cataracts and an increased incidence of cancer . RECQL4 mutant mice also show features of accelerated aging. RECQL4 has a crucial role in DNA end resection that is the initial step required for homologous recombination (HR)-dependent double-strand break repair. When RECQL4

1860-477: The dnaQ gene encodes the ε subunit of DNA polymerase III . The ε subunit is one of three core proteins of the DNA polymerase complex. It acts as a 3’→5’ DNA directed proofreading exonuclease that removes incorrectly incorporated bases during replication. Similarly, in Salmonella typhimurium bacteria, the 3’ to 5’ editing function employed during DNA replication is also encoded by a gene, dnaQ , which specifies

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1920-560: The genomes of an asexual population tend to accumulate more deleterious mutations over time than beneficial or reversing mutations. Chromosomal crossover involves recombination between the paired chromosomes inherited from each of one's parents, generally occurring during meiosis . During prophase I (pachytene stage) the four available chromatids are in tight formation with one another. While in this formation, homologous sites on two chromatids can closely pair with one another, and may exchange genetic information. Because there

1980-420: The immune system perform genetic recombination, called immunoglobulin class switching . It is a biological mechanism that changes an antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG . In genetic engineering , recombination can also refer to artificial and deliberate recombination of disparate pieces of DNA, often from different organisms, creating what

2040-467: The mouse and Caenorhabditis elegans . This protein has not been found in yeast, which suggests that it is likely to have an abnormal exonuclease domain like the one seen in a metazoan. Yeast contains Rat1 and Xrn1 exonuclease. The Rat1 works just like the human type (Xrn2) and Xrn1 function in the cytoplasm is in the 5' to 3' direction to degrade RNAs (pre-5.8s and 25s rRNAs) in the absence of Rat1. In beta Coronaviruses , including SARS-CoV-2 ,

2100-508: The poliovirus RNA-dependent RNA polymerase (RdRp) is able to carry out recombination. Recombination appears to occur by a copy choice mechanism in which the RdRp switches (+)ssRNA templates during negative strand synthesis. Recombination by RdRp strand switching also occurs in the (+)ssRNA plant carmoviruses and tombusviruses . Recombination appears to be a major driving force in determining genetic variability within coronaviruses, as well as

2160-466: The Bloom syndrome (BLM) protein that is designated Sgs1 (Small growth suppressor 1). Sgs1(BLM) is a helicase that functions in homologous recombinational repair of DNA double-strand breaks. The Sgs1(BLM) helicase appears to be a central regulator of most of the recombination events that occur during S. cerevisiae meiosis . During normal meiosis Sgs1(BLM) is responsible for directing recombination towards

2220-562: The N-terminal region is involved in the suppression of spontaneous and damage induced recombination and the absence of this interaction results in a lethal or very severe phenotype. The emerging picture clearly is that RecQ helicases in concert with Top 3 are involved in maintaining genomic stability and integrity by controlling recombination events, and repairing DNA damage in the G2-phase of the cell cycle. The importance of RecQ for genomic integrity

2280-549: The N-terminal residues (Helicase and, RecQ-Ct domains) impairs both helicase and ATPase activity but has no effect on the binding ability of RecQ implying that the N-terminus functions as the catalytic end. Truncations of the C-terminus (HRDC domain) compromise the binding ability of RecQ but not the catalytic function. The importance of RecQ in cellular functions is exemplified by human diseases, which all lead to genomic instability and

2340-398: The RNA primer contained immediately upstream from the site of DNA synthesis in a 5' → 3' manner. Exonuclease III has four catalytic activities: Exonuclease IV adds a water molecule, so it can break the bond of an oligonucleotide to nucleoside 5' monophosphate. This exonuclease requires Mg 2+ in order to function and works at higher temperatures than exonuclease I. Exonuclease V

2400-512: The ability of coronavirus species to jump from one host to another and, infrequently, for the emergence of novel species, although the mechanism of recombination in is unclear. In early 2020, many genomic sequences of Australian SARS‐CoV‐2 isolates have deletions or mutations (29742G>A or 29742G>U; "G19A" or "G19U") in the s2m, suggesting that RNA recombination may have occurred in this RNA element. 29742G("G19"), 29744G("G21"), and 29751G("G28") were predicted as recombination hotspots. During

2460-523: The alternate formation of either early non-crossovers or Holliday junction joint molecules, the latter being subsequently resolved as crossovers . In the plant Arabidopsis thaliana , homologs of the Sgs1(BLM) helicase act as major barriers to meiotic crossover formation. These helicases are thought to displace the invading strand allowing its annealing with the other 3'overhang end of the double-strand break, leading to non-crossover recombinant formation by

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2520-403: The arms of the chromosomes flanking the recombination event remain in the parental configuration. Thus, explanations for the adaptive function of meiosis that focus exclusively on crossing-over are inadequate to explain the majority of recombination events. Achiasmy is the phenomenon where autosomal recombination is completely absent in one sex of a species. Achiasmatic chromosomal segregation

2580-701: The bacterial RecA protein is RadA. Bacteria regularly undergo genetic recombination in three main ways: Sometimes a strand of DNA is transferred into the target cell but fails to be copied as the target divides. This is called an abortive transfer . In eukaryotes , recombination during meiosis is facilitated by chromosomal crossover . The crossover process leads to offspring having different combinations of genes from those of their parents, and can occasionally produce new chimeric alleles . The shuffling of genes brought about by genetic recombination produces increased genetic variation . It also allows sexually reproducing organisms to avoid Muller's ratchet , in which

2640-400: The case of pathogenic viruses, multiplicity reactivation may be an adaptive benefit to the virus since it allows the repair of DNA damages caused by exposure to the oxidizing environment produced during host infection. See also reassortment . A molecular model for the mechanism of meiotic recombination presented by Anderson and Sekelsky is outlined in the first figure in this article. Two of

2700-453: The chief recombinase found in Escherichia coli , is responsible for the repair of DNA double strand breaks (DSBs). In yeast and other eukaryotic organisms there are two recombinases required for repairing DSBs. The RAD51 protein is required for mitotic and meiotic recombination, whereas the DNA repair protein, DMC1 , is specific to meiotic recombination. In the archaea, the ortholog of

2760-619: The first months of the COVID-19 pandemic, such a recombination event was suggested to have been a critical step in the evolution of SARS-CoV-2's ability to infect humans. Linkage disequilibrium analysis confirmed that RNA recombination with the 11083G > T mutation also contributed to the increase of mutations among the viral progeny. The findings indicate that the 11083G > T mutation of SARS-CoV-2 spread during Diamond Princess shipboard quarantine and arose through de novo RNA recombination under positive selection pressure. In three patients on

2820-543: The four chromatids present early in meiosis (prophase I) are paired with each other and able to interact. Recombination, in this model, is initiated by a double-strand break (or gap) shown in the DNA molecule (chromatid) at the top of the figure. Other types of DNA damage may also initiate recombination. For instance, an inter-strand cross-link (caused by exposure to a cross-linking agent such as mitomycin C) can be repaired by HRR. Two types of recombinant product are produced. Indicated on

2880-420: The origin of life ( abiogenesis ) is also the origin of biological evolution . They pointed out that all known life on earth is based on biopolymers and proposed that any theory for the origin of life must involve biological polymers that act as information carriers and catalysts. Lehman argued that recombination was an evolutionary development as ancient as the origins of life. Smail et al. proposed that in

2940-613: The pairing of homologous chromosomes . This may be followed by information transfer between the chromosomes. The information transfer may occur without physical exchange (a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed) (see SDSA – Synthesis Dependent Strand Annealing pathway in Figure); or by the breaking and rejoining of DNA strands, which forms new molecules of DNA (see DHJ pathway in Figure). Recombination may also occur during mitosis in eukaryotes where it ordinarily involves

3000-626: The positive correlation of recombination events over short distances in organisms with a DNA genome (see first Figure, SDSA pathway). Recombination can occur infrequently between animal viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans. Especially in coronaviruses, recombination may also occur even among distantly related evolutionary groups (subgenera), due to their characteristic transcription mechanism, that involves subgenomic mRNAs that are formed by template switching. When replicating its (+)ssRNA genome ,

3060-426: The primordial Earth, recombination played a key role in the expansion of the initially short informational polymers (presumed to be RNA ) that were the precursors to life. [REDACTED]  This article incorporates public domain material from Science Primer . NCBI . Archived from the original on 2009-12-08. Exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at

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3120-429: The product until it is completely degraded. This allows the nucleotides to be recycled. Xrn1 is linked to a co-transcriptional cleavage (CoTC) activity that acts as a precursor to develop a free 5' unprotected end, so the exonuclease can remove and degrade the downstream cleavage product (DCP). This initiates transcriptional termination because one does not want DNA or RNA strands building up in their bodies. CCR4-Not

3180-413: The production of genetic maps . In gene conversion, a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed. Gene conversion occurs at high frequency at the actual site of the recombination event during meiosis . It is a process by which a DNA sequence is copied from one DNA helix (which remains unchanged) to another DNA helix, whose sequence

3240-427: The right side is a "crossover" (CO) type, where the flanking regions of the chromosomes are exchanged, and on the left side, a "non-crossover" (NCO) type where the flanking regions are not exchanged. The CO type of recombination involves the intermediate formation of two "Holliday junctions" indicated in the lower right of the figure by two X-shaped structures in each of which there is an exchange of single strands between

3300-426: The risk of cancer (see DNA repair-deficiency disorder ). In bacteria, transformation is a process of gene transfer that ordinarily occurs between individual cells of the same bacterial species. Transformation involves integration of donor DNA into the recipient chromosome by recombination. This process appears to be an adaptation for repairing DNA damages in the recipient chromosome by HRR. Transformation may provide

3360-430: The same host cell. Recombination is largely responsible for RNA virus diversity and immune evasion. RNA recombination appears to be a major driving force in determining genome architecture and the course of viral evolution among picornaviridae ( (+)ssRNA ) (e.g. poliovirus ). In the retroviridae ((+)ssRNA)(e.g. HIV ), damage in the RNA genome appears to be avoided during reverse transcription by strand switching,

3420-429: The separation of the DNA polymerase gene function from the 3’ to 5’ exonuclease editing gene function in the lineage that led to E. coli and S. typhimurium . The 3' to 5' human type endonuclease is known to be essential for the proper processing of histone pre-mRNA, in which U7 snRNP directs the single cleavage process. Following the removal of the downstream cleavage product (DCP) Xrn1 continues to further breakdown

3480-573: The two participating chromatids. This pathway is labeled in the figure as the DHJ (double-Holliday junction) pathway. The NCO recombinants (illustrated on the left in the figure) are produced by a process referred to as "synthesis dependent strand annealing" (SDSA). Recombination events of the NCO/SDSA type appear to be more common than the CO/DHJ type. The NCO/SDSA pathway contributes little to genetic variation, since

3540-509: The two sister chromosomes formed after chromosomal replication. In this case, new combinations of alleles are not produced since the sister chromosomes are usually identical. In meiosis and mitosis, recombination occurs between similar molecules of DNA ( homologous sequences ). In meiosis, non-sister homologous chromosomes pair with each other so that recombination characteristically occurs between non-sister homologues. In both meiotic and mitotic cells, recombination between homologous chromosomes

3600-548: Was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress , particularly in slowly replicating cells. This finding suggested that WRN may be important in dealing with oxidative DNA damages that underlie normal aging (see DNA damage theory of aging ). Cells from humans with Bloom syndrome are sensitive to DNA damaging agents such as UV and methyl methanesulfonate indicating deficient DNA repair capability. The budding yeast Saccharomyces cerevisiae encodes an ortholog of

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