TY - JOUR
T1 - Exploring the link between MORF4L1 and risk of breast cancer
AU - Martrat, Griselda
AU - Maxwell, Christopher A.
AU - Tominaga, Emiko
AU - Porta-de-la-Riva, Montserrat
AU - Bonifaci, Nuria
AU - Gomez-Baldo, Laia
AU - Bogliolo, Massimo
AU - Lazaro, Conxi
AU - Blanco, Ignacio
AU - Brunet, Joan
AU - Aguilar, Helena
AU - Fernandez-Rodriguez, Juana
AU - Seal, Sheila
AU - Renwick, Anthony
AU - Rahman, Nazneen
AU - Kuehl, Julia
AU - Neveling, Kornelia
AU - Schindler, Detlev
AU - Ramirez, Maria J.
AU - Castella, Maria
AU - Hernandez, Gonzalo
AU - Easton, Douglas F.
AU - Peock, Susan
AU - Cook, Margaret
AU - Oliver, Clare T.
AU - Frost, Debra
AU - Platte, Radka
AU - Evans, D. Gareth
AU - Lalloo, Fiona
AU - Eeles, Rosalind
AU - Izatt, Louise
AU - Chu, Carol
AU - Davidson, Rosemarie
AU - Ong, Kai-ren
AU - Cook, Jackie
AU - Douglas, Fiona
AU - Hodgson, Shirley V.
AU - Brewer, Carole
AU - Morrison, Patrick J.
AU - Porteous, Mary E.
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Peissel, Bernard
AU - Zaffaroni, Daniela
AU - Roversi, Gaia
AU - Barile, Monica
AU - Viel, Alessandra
AU - Blok, Marinus J.
AU - HEBON
AU - van Roozendaal, Kees
AU - Gomez Garcia, Encarna
AU - Tominaga, Kaoru
AU - Surrallés, Jordi
AU - Pujana, Miguel A.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - 10.1186/bcr2862
DO - 10.1186/bcr2862
M3 - Article
C2 - 21466675
SN - 1465-5411
VL - 13
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 2
ER -