RAD51C

The RAD51C protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.{{cite journal | vauthors = Miller KA, Sawicka D, Barsky D, Albala JS | title = Domain mapping of the Rad51 paralog protein complexes | journal = Nucleic Acids Research | volume = 32 | issue = 1 | pages = 169–78 | year = 2004 | pmid = 14704354 | pmc = 373258 | doi = 10.1093/nar/gkg925 }}

The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.{{cite journal | vauthors = Chun J, Buechelmaier ES, Powell SN | title = Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway | journal = Molecular and Cellular Biology | volume = 33 | issue = 2 | pages = 387–95 | date = January 2013 | pmid = 23149936 | pmc = 3554112 | doi = 10.1128/MCB.00465-12 }}

RAD51C forms two distinct complexes with other related paralogs: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.

The CX3 complex acts downstream of RAD51 recruitment to damage sites. The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.

The RAD51C gene of rice has an essential role in meiosis in both male and female gametocytes.{{cite journal |vauthors=Kou Y, Chang Y, Li X, Xiao J, Wang S |title=The rice RAD51C gene is required for the meiosis of both female and male gametocytes and the repair of DNA damage in somatic cells |journal=J Exp Bot |volume=63 |issue=14 |pages=5323–35 |date=September 2012 |pmid=22859673 |pmc=3431001 |doi=10.1093/jxb/ers190 |url=}} RAD51C is also required for repair of DNA damage in rice somatic cells.

The RAD51C gene is one of genes four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing has been observed for this gene and two variants encoding different isoforms have been identified.{{Cite web| title = Entrez Gene: RAD51C RAD51 homolog C (S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5889}}

A characteristic of many cancer cells is that parts of some genes contained within these cells have been recombined with other genes. One such gene fusion that has been identified in a MCF-7 breast cancer cell line is a chimera between the RAD51C and ATXN7 genes.{{Cite web| url =https://www.nytimes.com/2008/12/25/science/25visual.html | title = The Chaos Inside a Cancer Cell | author = Wade N | date = 2008-12-25 | work = Science Visuals | publisher = NYTimes.com | access-date = 2008-12-29}}{{cite journal | vauthors = Hampton OA, Den Hollander P, Miller CA, Delgado DA, Li J, Coarfa C, Harris RA, Richards S, Scherer SE, Muzny DM, Gibbs RA, Lee AV, Milosavljevic A | title = A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome | journal = Genome Research | volume = 19 | issue = 2 | pages = 167–77 | date = February 2009 | pmid = 19056696 | pmc = 2652200 | doi = 10.1101/gr.080259.108 }} Since the RAD51C protein is involved in repairing double strand chromosome breaks, this chromosomal rearrangement could be responsible for the other rearrangements.

RAD51C mutation increases the risk for breast and ovarian cancer, and was first established as a human cancer susceptibility gene in 2010.{{cite journal | vauthors = Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H | title = Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene | journal = Nature Genetics | volume = 42 | issue = 5 | pages = 410–4 | date = May 2010 | pmid = 20400964 | doi = 10.1038/ng.569 | s2cid = 23842635 }}{{cite journal | vauthors = Clague J, Wilhoite G, Adamson A, Bailis A, Weitzel JN, Neuhausen SL | title = RAD51C germline mutations in breast and ovarian cancer cases from high-risk families | journal = PLOS ONE | volume = 6 | issue = 9 | pages = e25632 | year = 2011 | pmid = 21980511 | pmc = 3182241 | doi = 10.1371/journal.pone.0025632 | bibcode = 2011PLoSO...625632C | doi-access = free }}{{cite journal | vauthors = Jønson L, Ahlborn LB, Steffensen AY, Djursby M, Ejlertsen B, Timshel S, Nielsen FC, Gerdes AM, Hansen TV | title = Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer | journal = Breast Cancer Research and Treatment | volume = 155 | issue = 2 | pages = 215–22 | date = January 2016 | pmid = 26740214 | doi = 10.1007/s10549-015-3674-y | s2cid = 2889495 }} Carriers of an RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene.{{cite journal | vauthors = Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, Høgdall CK, Jensen A, Kjaer SK, Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Odunsi K, Goode EL, Menon U, Jacobs IJ, Gayther SA, Pharoah PD | title = Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population | journal = Journal of Clinical Oncology | volume = 33 | issue = 26 | pages = 2901–7 | date = September 2015 | pmid = 26261251 | doi = 10.1200/JCO.2015.61.2408 | pmc = 4554751 }} A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15%.{{cite journal | vauthors = Sopik V, Akbari MR, Narod SA | title = Genetic testing for RAD51C mutations: in the clinic and community | journal = Clinical Genetics | volume = 88 | issue = 4 | pages = 303–12 | date = October 2015 | pmid = 25470109 | doi = 10.1111/cge.12548 | s2cid = 44829446 }}{{cite journal | vauthors = Cunningham JM, Cicek MS, Larson NB, Davila J, Wang C, Larson MC, Song H, Dicks EM, Harrington P, Wick M, Winterhoff BJ, Hamidi H, Konecny GE, Chien J, Bibikova M, Fan JB, Kalli KR, Lindor NM, Fridley BL, Pharoah PP, Goode EL | title = Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status | journal = Scientific Reports | volume = 4 | pages = 4026 | date = February 2014 | pmid = 24504028 | pmc = 4168524 | doi = 10.1038/srep04026 | bibcode = 2014NatSR...4E4026C }}{{cite journal | vauthors = Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM | title = Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas | journal = Clinical Cancer Research | volume = 20 | issue = 3 | pages = 764–75 | date = February 2014 | pmid = 24240112 | pmc = 3944197 | doi = 10.1158/1078-0432.CCR-13-2287 }}{{cite journal | vauthors = Ring KL, Garcia C, Thomas MH, Modesitt SC | title = Current and future role of genetic screening in gynecologic malignancies | journal = American Journal of Obstetrics and Gynecology | volume = 217 | issue = 5 | pages = 512–521 | date = November 2017 | pmid = 28411145 | doi = 10.1016/j.ajog.2017.04.011 | s2cid = 29024566 }}

In addition, there are three other causes of RAD51C deficiency that also appear to increase cancer risk. These are alternative splicing, promoter methylation and repression by over-expression of EZH2.

Three alternatively spliced RAD51C transcripts were identified in colorectal cancers. Variant 1 is joined from the 3' end of exon-6 to the 5' end of exon-8, variant 2 is joined at the 3' end of exon-5 to the 5' end of exon-8, and variant 3 is joined from the 3' end of exon-6 to the 5' end of exon-9.{{cite journal | vauthors = Kalvala A, Gao L, Aguila B, Reese T, Otterson GA, Villalona-Calero MA, Duan W | title = Overexpression of Rad51C splice variants in colorectal tumors | journal = Oncotarget | volume = 6 | issue = 11 | pages = 8777–87 | date = April 2015 | pmid = 25669972 | pmc = 4496183 | doi = 10.18632/oncotarget.3209 }} Presence and mRNA expression of variant 1 RAD51C was found in 47% of colorectal cancers. Variant 1 mRNA was expressed about 5-fold more frequently in colorectal tumors than in non-tumor tissues, and when present, was expressed 8-fold more frequently than wild-type RAD51C mRNA. The authors concluded that variant 1 mRNA was associated with the malignant phenotype of colorectal cancers

In the case of gastric cancer, reduced expression of RAD51C was found in about 40% to 50% of tumors, and almost all tumors with reduced RAD51C expression had methylation of the RAD51C promoter.{{cite journal | vauthors = Min A, Im SA, Yoon YK, Song SH, Nam HJ, Hur HS, Kim HP, Lee KH, Han SW, Oh DY, Kim TY, O'Connor MJ, Kim WH, Bang YJ | title = RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib | journal = Molecular Cancer Therapeutics | volume = 12 | issue = 6 | pages = 865–77 | date = June 2013 | pmid = 23512992 | doi = 10.1158/1535-7163.MCT-12-0950 | doi-access = free }} On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases.

EZH2 protein is up-regulated in numerous cancers.{{cite journal |author2-link=Mien-Chie Hung | vauthors = Chang CJ, Hung MC | title = The role of EZH2 in tumour progression | journal = British Journal of Cancer | volume = 106 | issue = 2 | pages = 243–7 | date = January 2012 | pmid = 22187039 | pmc = 3261672 | doi = 10.1038/bjc.2011.551 }}{{cite journal | vauthors = Völkel P, Dupret B, Le Bourhis X, Angrand PO | title = Diverse involvement of EZH2 in cancer epigenetics | journal = American Journal of Translational Research | volume = 7 | issue = 2 | pages = 175–93 | year = 2015 | pmid = 25901190 | pmc = 4399085 }} EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% and 75% of breast cancers have over-expressed EZH2 protein.{{cite journal | vauthors = Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM | title = EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 20 | pages = 11606–11 | date = September 2003 | pmid = 14500907 | pmc = 208805 | doi = 10.1073/pnas.1933744100 | bibcode = 2003PNAS..10011606K | doi-access = free }} EZH2 is the catalytic subunit of polycomb repressive complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates epigenetic gene silencing of target genes via local chromatin reorganization. EZH2 targets RAD51C, reducing RAD51C mRNA and protein expression (and also represses other RAD51 paralogs RAD51B, RAD51D, XRCC2 and XRCC3).{{cite journal | vauthors = Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, Kleer CG | title = The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells | journal = Neoplasia | volume = 7 | issue = 11 | pages = 1011–9 | date = November 2005 | pmid = 16331887 | pmc = 1502020 | doi = 10.1593/neo.05472 }} Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced homologous recombinational repair, was proposed as a cause of breast cancer.{{cite journal | vauthors = Zeidler M, Kleer CG | title = The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer | journal = Journal of Molecular Histology | volume = 37 | issue = 5–7 | pages = 219–23 | date = September 2006 | pmid = 16855786 | doi = 10.1007/s10735-006-9042-9 | s2cid = 2332105 }}

RAD51C has been shown to interact with:

• RAD51L1,{{cite journal | vauthors = Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P | title = Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange | journal = Genes & Development | volume = 15 | issue = 24 | pages = 3308–18 | date = December 2001 | pmid = 11751636 | pmc = 312844 | doi = 10.1101/gad.935501 }}
• RAD51L3, and
• XRCC2, and
• XRCC3.{{cite journal | vauthors = Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG | title = Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways | journal = Human Molecular Genetics | volume = 13 | issue = 12 | pages = 1241–8 | date = June 2004 | pmid = 15115758 | doi = 10.1093/hmg/ddh135 | doi-access = free }}{{cite journal | vauthors = Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS | title = RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 10 | pages = 8406–11 | date = March 2002 | pmid = 11744692 | doi = 10.1074/jbc.M108306200 | doi-access = free }}{{cite journal | vauthors = Liu N, Schild D, Thelen MP, Thompson LH | title = Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells | journal = Nucleic Acids Research | volume = 30 | issue = 4 | pages = 1009–15 | date = February 2002 | pmid = 11842113 | pmc = 100342 | doi = 10.1093/nar/30.4.1009 }}{{cite journal | vauthors = Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T | title = Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 10 | pages = 5538–43 | date = May 2001 | pmid = 11331762 | pmc = 33248 | doi = 10.1073/pnas.091603098 | doi-access = free }}

{{Reflist}}

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• {{cite journal | vauthors = Dosanjh MK, Collins DW, Fan W, Lennon GG, Albala JS, Shen Z, Schild D | title = Isolation and characterization of RAD51C, a new human member of the RAD51 family of related genes | journal = Nucleic Acids Research | volume = 26 | issue = 5 | pages = 1179–84 | date = March 1998 | pmid = 9469824 | pmc = 147393 | doi = 10.1093/nar/26.5.1179 }}
• {{cite journal | vauthors = Schild D, Lio YC, Collins DW, Tsomondo T, Chen DJ | title = Evidence for simultaneous protein interactions between human Rad51 paralogs | journal = The Journal of Biological Chemistry | volume = 275 | issue = 22 | pages = 16443–9 | date = June 2000 | pmid = 10749867 | doi = 10.1074/jbc.M001473200 | doi-access = free }}
• {{cite journal | vauthors = Avela K, Lipsanen-Nyman M, Idänheimo N, Seemanová E, Rosengren S, Mäkelä TP, Perheentupa J, Chapelle AD, Lehesjoki AE | title = Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 298–301 | date = July 2000 | pmid = 10888877 | doi = 10.1038/77053 | s2cid = 24257747 }}
• {{cite journal | vauthors = Bärlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G, Kallioniemi A | title = Multiple genes at 17q23 undergo amplification and overexpression in breast cancer | journal = Cancer Research | volume = 60 | issue = 19 | pages = 5340–4 | date = October 2000 | pmid = 11034067 }}
• {{cite journal | vauthors = Wu GJ, Sinclair CS, Paape J, Ingle JN, Roche PC, James CD, Couch FJ | title = 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes | journal = Cancer Research | volume = 60 | issue = 19 | pages = 5371–5 | date = October 2000 | pmid = 11034073 }}
• {{cite journal | vauthors = Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T | title = Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 10 | pages = 5538–43 | date = May 2001 | pmid = 11331762 | pmc = 33248 | doi = 10.1073/pnas.091603098 | doi-access = free }}
• {{cite journal | vauthors = Leasure CS, Chandler J, Gilbert DJ, Householder DB, Stephens R, Copeland NG, Jenkins NA, Sharan SK | title = Sequence, chromosomal location and expression analysis of the murine homologue of human RAD51L2/RAD51C | journal = Gene | volume = 271 | issue = 1 | pages = 59–67 | date = June 2001 | pmid = 11410366 | doi = 10.1016/S0378-1119(01)00498-X | url = https://zenodo.org/record/1260049 }}
• {{cite journal | vauthors = Masson JY, Stasiak AZ, Stasiak A, Benson FE, West SC | title = Complex formation by the human RAD51C and XRCC3 recombination repair proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 15 | pages = 8440–6 | date = July 2001 | pmid = 11459987 | pmc = 37455 | doi = 10.1073/pnas.111005698 | bibcode = 2001PNAS...98.8440M | doi-access = free }}
• {{cite journal | vauthors = Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS | title = RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 10 | pages = 8406–11 | date = March 2002 | pmid = 11744692 | doi = 10.1074/jbc.M108306200 | doi-access = free }}
• {{cite journal | vauthors = Masson JY, Tarsounas MC, Stasiak AZ, Stasiak A, Shah R, McIlwraith MJ, Benson FE, West SC | title = Identification and purification of two distinct complexes containing the five RAD51 paralogs | journal = Genes & Development | volume = 15 | issue = 24 | pages = 3296–307 | date = December 2001 | pmid = 11751635 | pmc = 312846 | doi = 10.1101/gad.947001 }}
• {{cite journal | vauthors = Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P | title = Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange | journal = Genes & Development | volume = 15 | issue = 24 | pages = 3308–18 | date = December 2001 | pmid = 11751636 | pmc = 312844 | doi = 10.1101/gad.935501 }}
• {{cite journal | vauthors = Wiese C, Collins DW, Albala JS, Thompson LH, Kronenberg A, Schild D | title = Interactions involving the Rad51 paralogs Rad51C and XRCC3 in human cells | journal = Nucleic Acids Research | volume = 30 | issue = 4 | pages = 1001–8 | date = February 2002 | pmid = 11842112 | pmc = 100332 | doi = 10.1093/nar/30.4.1001 }}
• {{cite journal | vauthors = Liu N, Schild D, Thelen MP, Thompson LH | title = Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells | journal = Nucleic Acids Research | volume = 30 | issue = 4 | pages = 1009–15 | date = February 2002 | pmid = 11842113 | pmc = 100342 | doi = 10.1093/nar/30.4.1009 }}
• {{cite journal | vauthors = Godthelp BC, Artwert F, Joenje H, Zdzienicka MZ | title = Impaired DNA damage-induced nuclear Rad51 foci formation uniquely characterizes Fanconi anemia group D1 | journal = Oncogene | volume = 21 | issue = 32 | pages = 5002–5 | date = July 2002 | pmid = 12118380 | doi = 10.1038/sj.onc.1205656 | doi-access = free }}
• {{cite journal | vauthors = Lio YC, Mazin AV, Kowalczykowski SC, Chen DJ | title = Complex formation by the human Rad51B and Rad51C DNA repair proteins and their activities in vitro | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2469–78 | date = January 2003 | pmid = 12427746 | doi = 10.1074/jbc.M211038200 | doi-access = free }}
• {{cite journal | vauthors = French CA, Tambini CE, Thacker J | title = Identification of functional domains in the RAD51L2 (RAD51C) protein and its requirement for gene conversion | journal = The Journal of Biological Chemistry | volume = 278 | issue = 46 | pages = 45445–50 | date = November 2003 | pmid = 12966089 | doi = 10.1074/jbc.M308621200 | doi-access = free }}
• {{cite journal | vauthors = Braybrooke JP, Li JL, Wu L, Caple F, Benson FE, Hickson ID | title = Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 48357–66 | date = November 2003 | pmid = 12975363 | doi = 10.1074/jbc.M308838200 | doi-access = free | hdl = 10026.1/10297 | hdl-access = free }}
• {{cite journal | vauthors = Miller KA, Sawicka D, Barsky D, Albala JS | title = Domain mapping of the Rad51 paralog protein complexes | journal = Nucleic Acids Research | volume = 32 | issue = 1 | pages = 169–78 | year = 2004 | pmid = 14704354 | pmc = 373258 | doi = 10.1093/nar/gkg925 }}
• {{cite journal | vauthors = Liu Y, Masson JY, Shah R, O'Regan P, West SC | title = RAD51C is required for Holliday junction processing in mammalian cells | journal = Science | volume = 303 | issue = 5655 | pages = 243–6 | date = January 2004 | pmid = 14716019 | doi = 10.1126/science.1093037 | bibcode = 2004Sci...303..243L | s2cid = 37077827 }}

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