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Updated: Jun 3, 2026
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Published on: October 16, 2010
Exploring the link between MORF4L1 and risk of breast cancer
Griselda Martrat1, Christopher M Maxwell, Emiko Tominaga
1Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran Via 199, L'Hospitalet del Llobregat 08908, Spain.
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, 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.
Insights
The study identified MRG15 as a protein involved in DNA double-strand break repair, interacting with key Fanconi anemia and breast cancer pathway proteins. While MRG15 plays a role in genomic stability, no significant mutations were found in FA patients or breast cancer families.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Fanconi anemia (FA) and breast cancer (BrCa) susceptibility genes are crucial in DNA damage repair.
- Investigating novel components of this pathway is key to understanding cancer risk.
Purpose of the Study:
- To identify novel proteins involved in the DNA damage repair pathway.
- To elucidate the role of MRG15 in DNA double-strand break repair and its association with cancer risk.
Main Methods:
- Yeast two-hybrid screens for protein interactions.
- Co-affinity purification and co-immunoprecipitation to confirm interactions.
- Functional assays in human, mouse, and C. elegans models.
- Genetic analysis of FA patients and familial breast cancer cases.
- Genotyping of common variants in BRCA1/2 mutation carriers.
Main Results:
- MRG15 (MORF4L1) was identified as a novel interacting protein in the DNA repair pathway.
- MRG15 plays a role in DNA double-strand break repair, influencing Rad51 foci formation and chromosomal stability.
- No mutations in MRG15/MORF4L1 were found in FA patients or familial breast cancer cases.
- No significant association between common MORF4L1 variants and breast cancer risk in BRCA1/2 carriers was observed.
Conclusions:
- MRG15 contributes to maintaining genomic stability.
- While MRG15 is involved in DNA repair, low-penetrance variants may have a weak association with breast cancer risk in BRCA2 carriers.
