Exploring the link between MORF4L1 and risk of breast cancer
Author
Summary, in English
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 g-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.
Department/s
- Breastcancer-genetics
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2011
Language
English
Publication/Series
Breast Cancer Research
Volume
13
Issue
2
Full text
Links
Document type
Journal article
Publisher
BioMed Central (BMC)
Topic
- Cancer and Oncology
Keywords
- Rad51 Recombinase
- RNA Interference
- Nuclear Proteins
- Mutation
- Mice
- Humans
- Genetic Predisposition to Disease
- BRCA2
- BRCA1
- Genes
- Female
- Fanconi Anemia Complementation Group D2 Protein
- Fanconi Anemia
- DNA Repair
- DNA Damage
- Cell Line
- Caenorhabditis elegans
- Animals
- Breast Neoplasms
- Replication Protein A
- Risk Factors
- Transcription Factors
- Tumor Suppressor Proteins
- Two-Hybrid System Techniques
Status
Published
ISBN/ISSN/Other
- ISSN: 1465-5411