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36-464: WRN may refer to: WRN (gene) , responsible for Werner syndrome West Runton railway station (UK railway station code) WRN Broadcast , formerly World Radio Network, an international broadcasting services company Polish Socialist Party - Freedom, Equality, Independence ( Polska Partia Socjalistyczna - Wolność, Równość, Niepodległość , PPS-WRN) Is not singular of WRNs: Women's Royal Naval Service ,

72-875: A synthetic lethality target in cancers containing a high number of microsatellites . These microsatellite-high (MSI-H) cancers have defects in their mismatch repair machinery (dMMR), which leads to the expansion of (TA)n dinucleotide repeats in the genome. These expanded (TA) dinucleotide microsatellites lead to the formation of secondary DNA structures (e.g. G-quadruplex ) and rely on WRN to repair these bulky lesions. Because of this therapeutic hypothesis, inhibition of WRN has become an area of high interest for targeted therapies of MSI-H cancers, especially those that do not respond to immune checkpoint inhibition or chemotherapy . Cells expressing limiting amounts of WRN have elevated mutation frequencies compared with wildtype cells. Increased mutation may give rise to cancer. Patients with Werner Syndrome, with homozygous mutations in

108-620: 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

144-480: 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

180-661: A common event in tumorigenesis. WRN is active in homologous recombination . Cells defective in the WRN gene have a 23-fold reduction in spontaneous mitotic recombination, with especial deficiency in conversion-type events. WRN defective cells, when exposed to x-rays, have more chromosome breaks and micronuclei than cells with wild-type WRN. Cells defective in the WRN gene are not more sensitive than wild-type cells to gamma-irradiation, UV light, 4 – 6 cyclobutane pyrimidines, or mitomycin C, but are sensitive to type I and type II topoisomerase inhibitors. These findings suggested that

216-565: A critical role in repairing DNA . Overall, this protein helps maintain the structure and integrity of a person's DNA. The WRN gene is located on the short (p) arm of chromosome 8 between positions 12 and 11.2, from base pair 31,010,319 to base pair 31,150,818. WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' exonuclease activity. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from

252-411: A fair degree of accuracy. WRN inhibits an alternative form of NHEJ, called alt-NHEJ or microhomology-mediated end joining (MMEJ). MMEJ is an inaccurate mode of repair for double-strand breaks. WRN has a role in base excision repair (BER) of DNA. As shown by Das et al., WRN associates with NEIL1 in the early damage-sensing step of BER. WRN stimulates NEIL1 in excision of oxidative lesions. NEIL1

288-463: A gap in dsDNA. WRN is important in repair of double strand breaks by homologous recombination or non-homologous end joining , repair of single nucleotide damages by base excision repair , and is effective in replication arrest recovery. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences. WRN is an oligomer that can act as

324-564: A monomer when unwinding DNA, but as a dimer in solution or a tetramer when complexed with DNA, and has also been observed in hexameric forms. The diffusion of WRN has been measured to 1.62 μ m 2 s {\displaystyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}} in nucleoplasm and 0.12 μ m 2 s {\displaystyle \textstyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}} at nucleoli. Orthologs of WRN have been found in

360-516: A number of other organisms, including Drosophila , Xenopus , and C. elegans . WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks. The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53 , an important tumor suppressor. WRN may function as an exonuclease in DNA repair, recombination, or replication, as well as resolution of DNA secondary structures. It

396-593: A small molecule in cancer cells harboring a high number of microsatellites (MSI-H), WRN becomes SUMOylated, which leads to is ubiquitylation and subsequent degradation. Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair. Werner syndrome is caused by mutations in the WRN gene. More than 20 mutations in the WRN gene are known to cause Werner syndrome. Many of these mutations result in an abnormally shortened Werner protein. Evidence suggests that

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432-410: 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

468-424: 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

504-544: Is a DNA glycosylase that initiates the first step in BER by cleaving bases damaged by reactive oxygen species (ROS) and introducing a DNA strand break via NEIL1's associated lyase activity. NEIL1 recognizes (targets) and removes certain ROS -damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines , formamidopyrimidines, thymine residues oxidized at

540-401: 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

576-411: 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

612-510: 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

648-572: Is also involved in replication arrest recovery. If WRN is defective, replication arrest results in accumulation of DSBs and enhanced chromosome fragmentation. As shown by Pichierri et al., WRN interacts with the RAD9 - RAD1 - HUS1 (9.1.1) complex, one of the central factors of the replication checkpoint. This interaction is mediated by the binding of the RAD1 subunit to the N-terminal region of WRN and

684-424: Is different from Wikidata All article disambiguation pages All disambiguation pages WRN (gene) 7486 22427 ENSG00000165392 ENSMUSG00000031583 Q14191 O09053 NM_000553 NM_001122822 NM_011721 NP_000544 NP_001116294 NP_035851 Werner syndrome ATP-dependent helicase , also known as DNA helicase, RecQ-like type 3 , is an enzyme that in humans

720-438: Is encoded by the WRN gene . WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA . These activities are necessary before DNA can be copied in preparation for cell division ( DNA replication ). Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription . Further evidence suggests that Werner protein plays

756-596: Is instrumental for WRN relocalization to nuclear foci and its phosphorylation in response to replication arrest. (In the absence of DNA damage or replication fork stalling, WRN protein remains localized to the nucleoli. ) The interaction of WRN with the 9.1.1 complex results in prevention of DSB formation at stalled replication forks. The p53 protein and WRN helicase engage in direct protein-protein interaction. Increased cellular WRN levels elicit increased cellular p53 levels and also potentiate p53-mediated apoptosis . This finding suggests that WRN helicase participates in

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792-532: Is involved in branch migration at Holliday junctions , and it interacts with other DNA replication intermediates. mRNA that codes for WRN has been identified in most human tissues. Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including SUMOylation and acetylation. Upon its inhibition by

828-408: 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

864-461: The WRN gene, have an increased incidence of cancers, including soft tissue sarcomas, osteosarcoma, thyroid cancer and melanoma. Mutations in WRN are rare in the general population. The rate of heterozygous loss-of-function mutation in WRN is approximately one per million. In a Japanese population the rate is 6 per 1,000, which is higher, but still infrequent. Mutational defects in the WRN gene are relatively rare in cancer cells compared to

900-483: 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

936-467: 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 ,

972-398: 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

1008-568: The WRN protein takes part in homologous recombinational repair and in the processing of stalled replication forks. WRN has an important role in non-homologous end joining (NHEJ) DNA repair. As shown by Shamanna et al., WRN is recruited to double-strand breaks (DSBs) and participates in NHEJ with its enzymatic and non-enzymatic functions. At DSBs, in association with Ku (protein) , it promotes standard or canonical NHEJ (c-NHEJ), repairing double-strand breaks in DNA with its enzymatic functions and with

1044-649: The activation of p53 in response to certain types of DNA damage . p53-mediated apoptosis is attenuated in cells from patients with Werner syndrome. Both repair of DNA damage and apoptosis are enzymatic processes necessary for maintaining integrity of the genome in humans. Cells with insufficient DNA repair tend to accumulate DNA damages, and when such cells are also defective in apoptosis they tend to survive even though excessive DNA damages are present. Replication of DNA in such deficient cells tends to lead to mutations and such mutations may cause cancer. Thus Werner syndrome helicase appears to have two roles related to

1080-551: The altered protein is not transported into the cell nucleus , where it normally interacts with DNA. This shortened protein may also be broken down too quickly, leading to a loss of Werner protein in the cell. Without normal Werner protein in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription. Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome. Recently, WRN has been identified as

1116-623: The former women's branch of the British Royal Navy Windarling Airport , IATA airport code "WRN" Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title WRN . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=WRN&oldid=1078712563 " Category : Disambiguation pages Hidden categories: Short description

WRN - Misplaced Pages Continue

1152-496: The frequency of epigenetic alterations in WRN that reduce WRN expression and could contribute to carcinogenesis. The situation is similar to other DNA repair genes whose expression is reduced in cancers due to mainly epigenetic alterations rather than mutations (see Frequencies of epimutations in DNA repair genes ). The table shows results of analysis of 630 human primary tumors for WRN CpG island hypermethylation. This hypermethylation caused reduced protein expression of WRN,

1188-413: The methyl group, and both stereoisomers of thymine glycol . WRN also participates in BER through its interaction with Polλ . WRN binds to the catalytic domain of Polλ and specifically stimulates DNA gap filling by Polλ over 8-oxo-G followed by strand displacement synthesis. This allows WRN to promote long-patch DNA repair synthesis by Polλ during MUTYH -initiated repair of 8-oxo-G:A mispairs. WRN

1224-428: The prevention of cancer, where the first role is to promote repair of specific types of damage and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell’s repair capability Merging with "Clinical significance" section Werner syndrome ATP-dependent helicase has been shown to interact with: Exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at

1260-429: 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

1296-429: 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

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