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Exploring the link between MORF4L1 and risk of breast cancer

Martrat, Griselda; Maxwell, Christopher A.; Tominaga, Emiko; Porta-de-la-Riva, Montserrat; Bonifaci, Nuria; Gomez-Baldo, Laia; Bogliolo, Massimo; Lazaro, Conxi; Blanco, Ignacio and Brunet, Joan, et al. (2011) In Breast Cancer Research 13(2).
Abstract
Introduction: 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... (More)
Introduction: 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 g-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, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 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. (Less)
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Rad51 Recombinase, RNA Interference, Nuclear Proteins, Mutation, Mice, Humans, Genetic Predisposition to Disease, BRCA2, BRCA1, Genes, Female, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia, DNA Repair, DNA Damage, Cell Line, Caenorhabditis elegans, Animals, Breast Neoplasms, Replication Protein A, Risk Factors, Transcription Factors, Tumor Suppressor Proteins, Two-Hybrid System Techniques
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Breast Cancer Research
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13
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2
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BioMed Central
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  • wos:000292694600029
  • scopus:84860405722
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1465-5411
DOI
10.1186/bcr2862
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English
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abfff1a4-5eb7-4fa1-bb7c-717d45d9b1fd (old id 2094273)
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http://dx.doi.org/10.1186/bcr2862
http://www.ncbi.nlm.nih.gov/pubmed/21466675
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2011-09-02 08:37:13
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2017-09-24 03:19:27
@article{abfff1a4-5eb7-4fa1-bb7c-717d45d9b1fd,
  abstract     = {Introduction: 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 g-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, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 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.},
  articleno    = {R40},
  author       = {Martrat, Griselda and Maxwell, Christopher A. and Tominaga, Emiko and Porta-de-la-Riva, Montserrat and Bonifaci, Nuria and Gomez-Baldo, Laia and Bogliolo, Massimo and Lazaro, Conxi and Blanco, Ignacio and Brunet, Joan and Aguilar, Helena and Fernandez-Rodriguez, Juana and Seal, Sheila and Renwick, Anthony and Rahman, Nazneen and Kuehl, Julia and Neveling, Kornelia and Schindler, Detlev and Ramirez, Maria J. and Castella, Maria and Hernandez, Gonzalo and Easton, Douglas F. and Peock, Susan and Cook, Margaret and Oliver, Clare T. and Frost, Debra and Platte, Radka and Evans, D. Gareth and Lalloo, Fiona and Eeles, Rosalind and Izatt, Louise and Chu, Carol and Davidson, Rosemarie and Ong, Kai-Ren and Cook, Jackie and Douglas, Fiona and Hodgson, Shirley and Brewer, Carole and Morrison, Patrick J. and Porteous, Mary and Peterlongo, Paolo and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Roversi, Gaia and Barile, Monica and Viel, Alessandra and Pasini, Barbara and Ottini, Laura and Putignano, Anna Laura and Savarese, Antonella and Bernard, Loris and Radice, Paolo and Healey, Sue and Spurdle, Amanda and Chen, Xiaoqing and Beesley, Jonathan and Rookus, Matti A. and Verhoef, Senno and Tilanus-Linthorst, Madeleine A. and Vreeswijk, Maaike P. and Asperen, Christi J. and Bodmer, Danielle and Ausems, Margreet G. E. M. and van Os, Theo A. and Blok, Marinus J. and Meijers-Heijboer, Hanne E. J. and Hogervorst, Frans B. L. and Goldgar, David E. and Buys, Saundra and John, Esther M. and Miron, Alexander and Southey, Melissa and Daly, Mary B. and Harbst, Katja and Borg, Åke and Rantala, Johanna and Barbany-Bustinza, Gisela and Ehrencrona, Hans and Stenmark-Askmalm, Marie and Kaufman, Bella and Laitman, Yael and Milgrom, Roni and Friedman, Eitan and Domchek, Susan M. and Nathanson, Katherine L. and Rebbeck, Timothy R. and Johannsson, Oskar Thor and Couch, Fergus J. and Wang, Xianshu and Fredericksen, Zachary and Cuadras, Daniel and Moreno, Vctor and Pientka, Friederike K. and Depping, Reinhard and Caldes, Trinidad and Osorio, Ana and Benitez, Javier and Bueren, Juan and Heikkinen, Tuomas and Nevanlinna, Heli and Hamann, Ute and Torres, Diana and Caligo, Maria Adelaide and Godwin, Andrew K. and Imyanitov, Evgeny N. and Janavicius, Ramunas and Sinilnikova, Olga M. and Stoppa-Lyonnet, Dominique and Mazoyer, Sylvie and Verny-Pierre, Carole and Castera, Laurent and de Pauw, Antoine and Bignon, Yves-Jean and Uhrhammer, Nancy and Peyrat, Jean-Philippe and Vennin, Philippe and Ferrer, Sandra Fert and Collonge-Rame, Marie-Agnes and Mortemousque, Isabelle and McGuffog, Lesley and Chenevix-Trench, Georgia and Pereira-Smith, Olivia M. and Antoniou, Antonis C. and Ceron, Julian and Tominaga, Kaoru and Surralles, Jordi and Angel Pujana, Miguel},
  issn         = {1465-5411},
  keyword      = {Rad51 Recombinase,RNA Interference,Nuclear Proteins,Mutation,Mice,Humans,Genetic Predisposition to Disease,BRCA2,BRCA1,Genes,Female,Fanconi Anemia Complementation Group D2 Protein,Fanconi Anemia,DNA Repair,DNA Damage,Cell Line,Caenorhabditis elegans,Animals,Breast Neoplasms,Replication Protein A,Risk Factors,Transcription Factors,Tumor Suppressor Proteins,Two-Hybrid System Techniques},
  language     = {eng},
  number       = {2},
  publisher    = {BioMed Central},
  series       = {Breast Cancer Research},
  title        = {Exploring the link between MORF4L1 and risk of breast cancer},
  url          = {http://dx.doi.org/10.1186/bcr2862},
  volume       = {13},
  year         = {2011},
}