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Martrat, G; Maxwell, Ca; Tominaga, E; Porta-de-la-Riva, M; Bonifaci, N; Gómez-Baldó, L; Bogliolo, M; Lázaro, C; Blanco, I; Brunet, J; Aguilar, H; Fernández-Rodríguez, J; Seal, S; Renwick, A; Rahman, N; Kühl, J; Neveling, K; Schindler, D; Ramírez, Mj; Castellà, M; Hernández, G; Embrace,; Easton, Df; Peock, S; Cook, M; Oliver, Ct; Frost, D; Platte, R; Evans, Dg; Lalloo, F ... view all 134 authors View less authors (2011)
Publisher: BioMed Central
Journal: Breast Cancer Research : BCR
Languages: English
Types: Article
Subjects: Fanconi Anemia Complementation Group D2 Protein, Cancer och onkologi, Research Article, Transcription Factors, Breast Neoplasms, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, DNA Damage, Replication Protein A, Engineering and Technology, DNA Repair, Nuclear Proteins, Two-Hybrid System Techniques, Mice, Tumor Suppressor Proteins, BRCA1, Medicine(all), Animals, Female, Cell Line, BRCA2, Teknik och teknologier, Risk Factors, Fanconi Anemia, Genes, Caenorhabditis elegans, Cancer and Oncology, Rad51 Recombinase, Mutation, Genetic Predisposition to Disease, [SDV.CAN] Life Sciences [q-bio]/Cancer, RNA Interference, Humans
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. RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.