التفاصيل البيبلوغرافية
| العنوان: |
Exploring the link between MORF4L1 and risk of breast cancer. |
| المؤلفون: |
Martrat, Griselda, Maxwell, Christopher A., Tominaga, Emiko, Porta-de-la-Riva, Montserrat, Bonifaci, Núria, Gómez-Baldó, Laia, Bogliolo, Massimo, Lázaro, Conxi, Blanco, Ignacio, Brunet, Joan, Aguilar, Helena, Fernández-Rodríguez, Juana, Seal, Sheila, Renwick, Anthony, Rahman, Nazneen, Kühl, Julia, Neveling, Kornelia, Schindler, Detlev, Ramírez, María J., Castellà, María |
| المصدر: |
Breast Cancer Research; 2011, Vol. 13 Issue 3, p1-14, 14p, 2 Color Photographs, 1 Chart, 2 Graphs |
| مصطلحات موضوعية: |
BREAST cancer, FANCONI'S anemia, BIOLOGICAL assay, GENETIC mutation, LOCUS (Genetics) |
| مستخلص: |
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 BRCA½ mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA½ 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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