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.
Exploring the link between MORF4L1 and risk of breast cancer / Griselda, Martrat; Christopher A., Maxwell; Emiko, Tominaga; Montserrat Porta De La, Riva; Nuria, Bonifaci; Laia Gomez, Baldo; Massimo, Bogliolo; Conxi, Lazaro; Ignacio, Blanco; Joan, Brunet; Helena, Aguilar; Juana Fernandez, Rodriguez; Sheila, Seal; Anthony, Renwick; Nazneen, Rahman; Julia, Kuhl; Kornelia, Neveling; Detlev, Schindler; Maria J., Ramirez; Maria, Castella; Gonzalo, Hernandez; 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; Ottini, Laura; Anna, 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 Gem, Ausems; Theo A., Van Os; Marinus J., Blok; Hanne E. J., Meijers Heijboer; Frans B. L., Hogervorst; David E., Goldgar; Saundra, Buys; E. M., John; Alexander, Miron; Melissa, Southey; Mary B., Daly; Katja, Harbst; T., 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, Johannsson; Fergus J., Couch; Xianshu, Wang; Zachary, Fredericksen; Daniel, Cuadras; Víctor, Moreno; Friederike K., Pientka; Reinhard, Depping; Trinidad, Caldes; Ana, Osorio; Javier, Benitez; Juan, Bueren; Tuomas, Heikkinen; Heli, Nevanlinna; Ute, Hamann; Diana, Torres; Maria, 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, Ferrer; Marie Agnes Collonge, Rame; Isabelle, Mortemousque; Lesley, Mcguffog; Georgia Chenevix, Trench; Olivia M., Pereira Smith; Antonis C., Antoniou; Julián, Ceron; Kaoru, Tominaga; Jordi, Surralles; Miguel, Pujana. - In: BREAST CANCER RESEARCH. - ISSN 1465-5411. - 13:2(2011), pp. Art. n. R40-1-Art. n. R40-14. [10.1186/bcr2862]
Exploring the link between MORF4L1 and risk of breast cancer.
OTTINI, LAURA;
2011
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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
