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dc.contributor.authorMartrat, Griselda*
dc.contributor.authorMaxwell, Christopher M*
dc.contributor.authorTominaga, Emiko*
dc.contributor.authorPorta-de-la-Riva, Montserrat*
dc.contributor.authorBonifaci, Núria*
dc.contributor.authorGómez-Baldó, Laia*
dc.contributor.authorBogliolo, Massimo*
dc.contributor.authorLázaro, Conxi*
dc.contributor.authorBlanco, Ignacio*
dc.contributor.authorBrunet, Joan*
dc.contributor.authorAguilar, Helena*
dc.contributor.authorFernández-Rodríguez, Juana*
dc.contributor.authorSeal, Sheila*
dc.contributor.authorRenwick, Anthony*
dc.contributor.authorRahman, Nazneen*
dc.contributor.authorKühl, Julia*
dc.contributor.authorNeveling, Kornelia*
dc.contributor.authorSchindler, Detlev*
dc.contributor.authorRamírez, María J*
dc.contributor.authorCastellà, María*
dc.contributor.authorHernández, Gonzalo*
dc.contributor.authorEaston, Douglas F*
dc.contributor.authorPeock, Susan*
dc.contributor.authorCook, Margaret*
dc.contributor.authorOliver, Clare T*
dc.contributor.authorFrost, Debra*
dc.contributor.authorPlatte, Radka*
dc.contributor.authorEvans, D Gareth*
dc.contributor.authorLalloo, Fiona*
dc.contributor.authorEeles, Rosalind*
dc.contributor.authorIzatt, Louise*
dc.contributor.authorChu, Carol*
dc.contributor.authorDavidson, Rosemarie*
dc.contributor.authorOng, Kai-Ren*
dc.contributor.authorCook, Jackie*
dc.contributor.authorDouglas, Fiona*
dc.contributor.authorHodgson, Shirley*
dc.contributor.authorBrewer, Carole*
dc.contributor.authorMorrison, Patrick J*
dc.contributor.authorPorteous, Mary*
dc.contributor.authorPeterlongo, Paolo*
dc.contributor.authorManoukian, Siranoush*
dc.contributor.authorPeissel, Bernard*
dc.contributor.authorZaffaroni, Daniela*
dc.contributor.authorRoversi, Gaia*
dc.contributor.authorBarile, Monica*
dc.contributor.authorViel, Alessandra*
dc.contributor.authorPasini, Barbara*
dc.contributor.authorOttini, Laura*
dc.contributor.authorPutignano, Anna Laura*
dc.contributor.authorSavarese, Antonella*
dc.contributor.authorBernard, Loris*
dc.contributor.authorRadice, Paolo*
dc.contributor.authorHealey, Sue*
dc.contributor.authorSpurdle, Amanda*
dc.contributor.authorChen, Xiaoqing*
dc.contributor.authorBeesley, Jonathan*
dc.contributor.authorRookus, Matti A*
dc.contributor.authorVerhoef, Senno*
dc.contributor.authorTilanus-Linthorst, Madeleine A*
dc.contributor.authorVreeswijk, Maaike P*
dc.contributor.authorAsperen, Christi J*
dc.contributor.authorBodmer, Danielle*
dc.contributor.authorAusems, Margreet G E M*
dc.contributor.authorvan Os, Theo A*
dc.contributor.authorBlok, Marinus J*
dc.contributor.authorMeijers-Heijboer, Hanne E J*
dc.contributor.authorHogervorst, Frans B L*
dc.contributor.authorGoldgar, David E*
dc.contributor.authorBuys, Saundra*
dc.contributor.authorJohn, Esther M*
dc.contributor.authorMiron, Alexander*
dc.contributor.authorSouthey, Melissa*
dc.contributor.authorDaly, Mary B*
dc.contributor.authorHarbst, Katja*
dc.contributor.authorBorg, Ake*
dc.contributor.authorRantala, Johanna*
dc.contributor.authorBarbany-Bustinza, Gisela*
dc.contributor.authorEhrencrona, Hans*
dc.contributor.authorStenmark-Askmalm, Marie*
dc.contributor.authorKaufman, Bella*
dc.contributor.authorLaitman, Yael*
dc.contributor.authorMilgrom, Roni*
dc.contributor.authorFriedman, Eitan*
dc.contributor.authorDomchek, Susan M*
dc.contributor.authorNathanson, Katherine L*
dc.contributor.authorRebbeck, Timothy R*
dc.contributor.authorJohannsson, Oskar Thor*
dc.contributor.authorCouch, Fergus J*
dc.contributor.authorWang, Xianshu*
dc.contributor.authorFredericksen, Zachary*
dc.contributor.authorCuadras, Daniel*
dc.contributor.authorMoreno, Víctor*
dc.contributor.authorPientka, Friederike K*
dc.contributor.authorDepping, Reinhard*
dc.contributor.authorCaldés, Trinidad*
dc.contributor.authorOsorio, Ana*
dc.contributor.authorBenítez, Javier*
dc.contributor.authorBueren, Juan*
dc.contributor.authorHeikkinen, Tuomas*
dc.contributor.authorNevanlinna, Heli*
dc.contributor.authorHamann, Ute*
dc.contributor.authorTorres, Diana*
dc.contributor.authorCaligo, Maria Adelaide*
dc.contributor.authorGodwin, Andrew K*
dc.contributor.authorImyanitov, Evgeny N*
dc.contributor.authorJanavicius, Ramunas*
dc.contributor.authorSinilnikova, Olga M*
dc.contributor.authorStoppa-Lyonnet, Dominique*
dc.contributor.authorMazoyer, Sylvie*
dc.contributor.authorVerny-Pierre, Carole*
dc.contributor.authorCastera, Laurent*
dc.contributor.authorde Pauw, Antoine*
dc.contributor.authorBignon, Yves-Jean*
dc.contributor.authorUhrhammer, Nancy*
dc.contributor.authorPeyrat, Jean-Philippe*
dc.contributor.authorVennin, Philippe*
dc.contributor.authorFerrer, Sandra Fert*
dc.contributor.authorCollonge-Rame, Marie-Agnès*
dc.contributor.authorMortemousque, Isabelle*
dc.contributor.authorMcGuffog, Lesley*
dc.contributor.authorChenevix-Trench, Georgia*
dc.contributor.authorPereira-Smith, Olivia M*
dc.contributor.authorAntoniou, Antonis C*
dc.contributor.authorCerón, Julián*
dc.contributor.authorTominaga, Kaoru*
dc.contributor.authorSurrallés, Jordi*
dc.contributor.authorPujana, Miguel Angel*
dc.date.accessioned2012-06-04T11:45:37Z
dc.date.available2012-06-04T11:45:37Z
dc.date.issued2011
dc.date.submitted2012-06-04
dc.identifier.citationBreast Cancer Res. 2011, 13(2):R40en_GB
dc.identifier.issn1465-542X
dc.identifier.pmid21466675
dc.identifier.doi10.1186/bcr2862
dc.identifier.urihttp://hdl.handle.net/2336/227418
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links field.en_GB
dc.description.abstractINTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
dc.description.sponsorshipCancer Research - UKen_GB
dc.language.isoenen
dc.publisherBioMed Centralen_GB
dc.relation.urlhttp://dx.doi.org/10.1186/bcr2862en_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219203/?tool=pubmeden_GB
dc.rightsArchived with thanks to Breast cancer research : BCRen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshBreast Neoplasmsen_GB
dc.subject.meshCaenorhabditis elegansen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshDNA Damageen_GB
dc.subject.meshDNA Repairen_GB
dc.subject.meshFanconi Anemiaen_GB
dc.subject.meshFanconi Anemia Complementation Group D2 Proteinen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGenes, BRCA1en_GB
dc.subject.meshGenes, BRCA2en_GB
dc.subject.meshGenetic Predisposition to Diseaseen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMutationen_GB
dc.subject.meshNuclear Proteinsen_GB
dc.subject.meshRNA Interferenceen_GB
dc.subject.meshRad51 Recombinaseen_GB
dc.subject.meshReplication Protein Aen_GB
dc.subject.meshRisk Factorsen_GB
dc.subject.meshTranscription Factorsen_GB
dc.subject.meshTumor Suppressor Proteinsen_GB
dc.subject.meshTwo-Hybrid System Techniquesen_GB
dc.titleExploring the link between MORF4L1 and risk of breast cancer.en
dc.typeArticleen
dc.contributor.departmentTranslational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran Via 199, L'Hospitalet del Llobregat 08908, Spain.en_GB
dc.identifier.journalBreast cancer research : BCRen_GB
html.description.abstractINTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.


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