Exploring the link between MORF4L1 and risk of breast cancer

Griselda Martrat, Christopher A. Maxwell, Emiko Tominaga, Montserrat Porta-de-la-Riva, Núria Bonifaci, Laia Gómez-Baldó, Massimo Bogliolo, Conxi Lázaro, Ignacio Blanco, Joan Brunet, Helena Aguilar, Juana Fernández-Rodríguez, Sheila Seal, Anthony Renwick, Nazneen Rahman, Julia Kühl, Kornelia Neveling, Detlev Schindler, María J. Ramírez, María CastellàGonzalo Hernández, Douglas F. Easton, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Kai Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, Carole Brewer, Patrick J. Morrison, Mary Porteous, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Barbara Pasini, Laura Ottini, Anna L. Putignano, Antonella Savarese, Loris Bernard, Paolo Radice, Sue Healey, Amanda Spurdle, Xiaoqing Chen, Jonathan Beesley, Matti A. Rookus, Senno Verhoef, Madeleine A. Tilanus-Linthorst, Maaike P. Vreeswijk, Christi J. Asperen, Danielle Bodmer, Margreet G E M Ausems, Theo A. van Os, Marinus J. Blok, Hanne E J Meijers-Heijboer, Frans B L Hogervorst, David E. Goldgar, Saundra Buys, Esther M. John, Alexander Miron, Melissa Southey, Mary B. Daly, Katja Harbst, Åke Borg, Johanna Rantala, Gisela Barbany-Bustinza, Hans Ehrencrona, Marie Stenmark-Askmalm, Bella Kaufman, Yael Laitman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Oskar T. Johannsson, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Daniel Cuadras, Víctor Moreno, Friederike K. Pientka, Reinhard Depping, Trinidad Caldés, Ana Osorio, Javier Benítez, Juan Bueren, Tuomas Heikkinen, Heli Nevanlinna, Ute Hamann, Diana Torres, Maria A. Caligo, Andrew K. Godwin, Evgeny N. Imyanitov, Ramunas Janavicius, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine De Pauw, Yves Jean Bignon, Nancy Uhrhammer, Jean Philippe Peyrat, Philippe Vennin, Sandra F. Ferrer, Marie Agnès Collonge-Rame, Isabelle Mortemousque, Lesley McGuffog, Georgia Chenevix-Trench, Olivia M. Pereira-Smith, Antonis C. Antoniou, Julián Cerón, Kaoru Tominaga, Jordi Surrallés, Miguel A. Pujana

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    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 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, 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. © 2011 Martrat et al.; licensee BioMed Central Ltd.
    Original languageEnglish
    Article numberR40
    JournalBreast Cancer Research
    Issue number2
    Publication statusPublished - 5 Apr 2011


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