title: Exploring the link between MORF4L1 and risk of breast cancer.
abstract: BACKGROUND
  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, 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.
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran Via 199, L'Hospitalet del Llobregat 08908, Spain.
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mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; C470833:MORF4L1 protein, human; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C497167:RPA1 protein, human; D051716:Replication Protein A; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051135:Rad51 Recombinase