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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.

Exploring the link between MORF4L1 and risk of breast cancer