Exploring the link between MORF4L1 and risk of breast cancer

Griselda Martrat; Christopher A. Maxwell; Emiko Tominaga; Montserrat Porta-de-la-Riva; Núria Bonifaci; Laia Gómez-Baldó; Massimo Bogliolo; Conxi Lázaro; Ignacio Blanco; Joan Brunet; Helena Aguilar; Juana Fernández-Rodríguez; Sheila Seal; Anthony Renwick; Nazneen Rahman; Julia Kühl; Kornelia Neveling; Detlev Schindler; María J. Ramírez; María Castellà; Gonzalo Hernández; Douglas F. Easton; Susan Peock; Margaret Cook; Clare T. Oliver; Debra Frost; Radka Platte; D. Gareth Evans; Fiona Lalloo; Rosalind Eeles; Louise Izatt; Carol Chu; Rosemarie Davidson; Kai Ren Ong; Jackie Cook; Fiona Douglas; Shirley Hodgson; Carole Brewer; Patrick J. Morrison; Mary Porteous; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Daniela Zaffaroni; Gaia Roversi; Monica Barile; Alessandra Viel; Barbara Pasini; Laura Ottini; Anna L. Putignano; Antonella Savarese; Loris Bernard; Paolo Radice; Sue Healey; Amanda Spurdle; Xiaoqing Chen; Jonathan Beesley; Matti A. Rookus; Senno Verhoef; Madeleine A. Tilanus-Linthorst; Maaike P. Vreeswijk; Christi J. Asperen; Danielle Bodmer; Margreet G.E.M. Ausems; Theo A. van Os; Marinus J. Blok; Hanne E.J. Meijers-Heijboer; Frans B.L. Hogervorst; David E. Goldgar; Saundra Buys; Esther M. John; Alexander Miron; Melissa Southey; Mary B. Daly; Katja Harbst; Åke Borg; Johanna Rantala; Gisela Barbany-Bustinza; Hans Ehrencrona; Marie Stenmark-Askmalm; Bella Kaufman; Yael Laitman; Roni Milgrom; Eitan Friedman; Susan M. Domchek; Katherine L. Nathanson; Timothy R. Rebbeck; Oskar T. Johannsson; Fergus J. Couch; Xianshu Wang; Zachary Fredericksen; Daniel Cuadras; Víctor Moreno; Friederike K. Pientka; Reinhard Depping; Trinidad Caldés; Ana Osorio; Javier Benítez; Juan Bueren; Tuomas Heikkinen; Heli Nevanlinna; Ute Hamann; Diana Torres; Maria A. Caligo; Andrew K. Godwin; Evgeny N. Imyanitov; Ramunas Janavicius; Olga M. Sinilnikova; Dominique Stoppa-Lyonnet; Sylvie Mazoyer; Carole Verny-Pierre; Laurent Castera; Antoine De Pauw; Yves Jean Bignon; Nancy Uhrhammer; Jean Philippe Peyrat; Philippe Vennin; Sandra F. Ferrer; Marie Agnès Collonge-Rame; Isabelle Mortemousque; Lesley McGuffog; Georgia Chenevix-Trench; Olivia M. Pereira-Smith; Antonis C. Antoniou; Julián Cerón; Kaoru Tominaga; Jordi Surrallés; Miguel A. Pujana

doi:10.1186/bcr2862

Exploring the link between MORF4L1 and risk of breast cancer

Griselda Martrat, Christopher A. Maxwell, Emiko Tominaga, Montserrat Porta-de-la-Riva, Núria Bonifaci, Laia Gómez-Baldó, Massimo Bogliolo, Conxi Lázaro, Ignacio Blanco, Joan Brunet, Helena Aguilar, Juana Fernández-Rodríguez, Sheila Seal, Anthony Renwick, Nazneen Rahman, Julia Kühl, Kornelia Neveling, Detlev Schindler, María J. Ramírez, María CastellàGonzalo Hernández, Douglas F. Easton, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Kai Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, Carole Brewer, Patrick J. Morrison, Mary Porteous, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Barbara Pasini, Laura Ottini, Anna L. Putignano, Antonella Savarese, Loris Bernard, Paolo Radice, Sue Healey, Amanda Spurdle, Xiaoqing Chen, Jonathan Beesley, Matti A. Rookus, Senno Verhoef, Madeleine A. Tilanus-Linthorst, Maaike P. Vreeswijk, Christi J. Asperen, Danielle Bodmer, Margreet G.E.M. Ausems, Theo A. van Os, Marinus J. Blok, Hanne E.J. Meijers-Heijboer, Frans B.L. Hogervorst, David E. Goldgar, Saundra Buys, Esther M. John, Alexander Miron, Melissa Southey, Mary B. Daly, Katja Harbst, Åke Borg, Johanna Rantala, Gisela Barbany-Bustinza, Hans Ehrencrona, Marie Stenmark-Askmalm, Bella Kaufman, Yael Laitman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Oskar T. Johannsson, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Daniel Cuadras, Víctor Moreno, Friederike K. Pientka, Reinhard Depping, Trinidad Caldés, Ana Osorio, Javier Benítez, Juan Bueren, Tuomas Heikkinen, Heli Nevanlinna, Ute Hamann, Diana Torres, Maria A. Caligo, Andrew K. Godwin, Evgeny N. Imyanitov, Ramunas Janavicius, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine De Pauw, Yves Jean Bignon, Nancy Uhrhammer, Jean Philippe Peyrat, Philippe Vennin, Sandra F. Ferrer, Marie Agnès Collonge-Rame, Isabelle Mortemousque, Lesley McGuffog, Georgia Chenevix-Trench, Olivia M. Pereira-Smith, Antonis C. Antoniou, Julián Cerón^*, Kaoru Tominaga, Jordi Surrallés, Miguel A. Pujana

^*Corresponding author for this work

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Research output: Contribution to journal › Article › peer-review

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Abstract

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, 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.

Original language	English
Article number	R40
Journal	Breast Cancer Research
Volume	13
Issue number	2
DOIs	https://doi.org/10.1186/bcr2862
State	Published - 5 Apr 2011

Funding

Funders	Funder number
National Institute on Aging	R01AG032134
Cancer Research UK

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/bcr2862

Cite this

Martrat, G., Maxwell, C. A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gómez-Baldó, L., Bogliolo, M., Lázaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernández-Rodríguez, J., Seal, S., Renwick, A., Rahman, N., Kühl, J., Neveling, K., Schindler, D., Ramírez, M. J., ... Pujana, M. A. (2011). Exploring the link between MORF4L1 and risk of breast cancer. Breast Cancer Research, 13(2), Article R40. https://doi.org/10.1186/bcr2862

@article{daf7e32b913443bdab541b6562fab2c2,

title = "Exploring the link between MORF4L1 and risk of breast cancer",

abstract = "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, 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.",

author = "Griselda Martrat and Maxwell, {Christopher A.} and Emiko Tominaga and Montserrat Porta-de-la-Riva and N{\'u}ria Bonifaci and Laia G{\'o}mez-Bald{\'o} and Massimo Bogliolo and Conxi L{\'a}zaro and Ignacio Blanco and Joan Brunet and Helena Aguilar and Juana Fern{\'a}ndez-Rodr{\'i}guez and Sheila Seal and Anthony Renwick and Nazneen Rahman and Julia K{\"u}hl and Kornelia Neveling and Detlev Schindler and Ram{\'i}rez, {Mar{\'i}a J.} and Mar{\'i}a Castell{\`a} and Gonzalo Hern{\'a}ndez and Easton, {Douglas F.} and Susan Peock and Margaret Cook and Oliver, {Clare T.} and Debra Frost and Radka Platte and Evans, {D. Gareth} and Fiona Lalloo and Rosalind Eeles and Louise Izatt and Carol Chu and Rosemarie Davidson and Ong, {Kai Ren} and Jackie Cook and Fiona Douglas and Shirley Hodgson and Carole Brewer and Morrison, {Patrick J.} and Mary Porteous and Paolo Peterlongo and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Gaia Roversi and Monica Barile and Alessandra Viel and Barbara Pasini and Laura Ottini and Putignano, {Anna L.} and Antonella Savarese and Loris Bernard and Paolo Radice and Sue Healey and Amanda Spurdle and Xiaoqing Chen and Jonathan Beesley and Rookus, {Matti A.} and Senno Verhoef and Tilanus-Linthorst, {Madeleine A.} and Vreeswijk, {Maaike P.} and Asperen, {Christi J.} and Danielle Bodmer and Ausems, {Margreet G.E.M.} and {van Os}, {Theo A.} and Blok, {Marinus J.} and Meijers-Heijboer, {Hanne E.J.} and Hogervorst, {Frans B.L.} and Goldgar, {David E.} and Saundra Buys and John, {Esther M.} and Alexander Miron and Melissa Southey and Daly, {Mary B.} and Katja Harbst and {\AA}ke Borg and Johanna Rantala and Gisela Barbany-Bustinza and Hans Ehrencrona and Marie Stenmark-Askmalm and Bella Kaufman and Yael Laitman and Roni Milgrom and Eitan Friedman and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Rebbeck, {Timothy R.} and Johannsson, {Oskar T.} and Couch, {Fergus J.} and Xianshu Wang and Zachary Fredericksen and Daniel Cuadras and V{\'i}ctor Moreno and Pientka, {Friederike K.} and Reinhard Depping and Trinidad Cald{\'e}s and Ana Osorio and Javier Ben{\'i}tez and Juan Bueren and Tuomas Heikkinen and Heli Nevanlinna and Ute Hamann and Diana Torres and Caligo, {Maria A.} and Godwin, {Andrew K.} and Imyanitov, {Evgeny N.} and Ramunas Janavicius and Sinilnikova, {Olga M.} and Dominique Stoppa-Lyonnet and Sylvie Mazoyer and Carole Verny-Pierre and Laurent Castera and {De Pauw}, Antoine and Bignon, {Yves Jean} and Nancy Uhrhammer and Peyrat, {Jean Philippe} and Philippe Vennin and Ferrer, {Sandra F.} and Collonge-Rame, {Marie Agn{\`e}s} and Isabelle Mortemousque and Lesley McGuffog and Georgia Chenevix-Trench and Pereira-Smith, {Olivia M.} and Antoniou, {Antonis C.} and Juli{\'a}n Cer{\'o}n and Kaoru Tominaga and Jordi Surrall{\'e}s and Pujana, {Miguel A.}",

note = "Funding Information: The authors thank Dr Andre Nussenzweig, Dr Laura Tusell and Dr Anton Gartner for providing Atm-deficient MEFs, anti-TRF2 and anti-RAD-51/RPA-1 antibodies, respectively. They also wish to thank all study participants, clinicians and centers for their valuable contribution, and the CGEMS initiative for making their genome-wide association study results available. The CIMBA data management is supported by Cancer Research - UK. Funding support is further detailed in Additional file 14.",

year = "2011",

month = apr,

day = "5",

doi = "10.1186/bcr2862",

language = "אנגלית",

volume = "13",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "2",

}

Martrat, G, Maxwell, CA, Tominaga, E, Porta-de-la-Riva, M, Bonifaci, N, Gómez-Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández-Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, MJ, Castellà, M, Hernández, G, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Platte, R, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, PJ, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, AL, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, MA, Verhoef, S, Tilanus-Linthorst, MA, Vreeswijk, MP, Asperen, CJ, Bodmer, D, Ausems, MGEM, van Os, TA, Blok, MJ, Meijers-Heijboer, HEJ, Hogervorst, FBL, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Harbst, K, Borg, Å, Rantala, J, Barbany-Bustinza, G, Ehrencrona, H, Stenmark-Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, SM, Nathanson, KL, Rebbeck, TR, Johannsson, OT, Couch, FJ, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, FK, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, MA, Godwin, AK, Imyanitov, EN, Janavicius, R, Sinilnikova, OM, Stoppa-Lyonnet, D, Mazoyer, S, Verny-Pierre, C, Castera, L, De Pauw, A, Bignon, YJ, Uhrhammer, N, Peyrat, JP, Vennin, P, Ferrer, SF, Collonge-Rame, MA, Mortemousque, I, McGuffog, L, Chenevix-Trench, G, Pereira-Smith, OM, Antoniou, AC, Cerón, J, Tominaga, K, Surrallés, J & Pujana, MA 2011, 'Exploring the link between MORF4L1 and risk of breast cancer', Breast Cancer Research, vol. 13, no. 2, R40. https://doi.org/10.1186/bcr2862

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, Núria

AU - Gómez-Baldó, Laia

AU - Bogliolo, Massimo

AU - Lázaro, Conxi

AU - Blanco, Ignacio

AU - Brunet, Joan

AU - Aguilar, Helena

AU - Fernández-Rodríguez, Juana

AU - Seal, Sheila

AU - Renwick, Anthony

AU - Rahman, Nazneen

AU - Kühl, Julia

AU - Neveling, Kornelia

AU - Schindler, Detlev

AU - Ramírez, María J.

AU - Castellà, María

AU - Hernández, 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

AU - Brewer, Carole

AU - Morrison, Patrick J.

AU - Porteous, Mary

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Roversi, Gaia

AU - Barile, Monica

AU - Viel, Alessandra

AU - Pasini, Barbara

AU - Ottini, Laura

AU - Putignano, Anna L.

AU - Savarese, Antonella

AU - Bernard, Loris

AU - Radice, Paolo

AU - Healey, Sue

AU - Spurdle, Amanda

AU - Chen, Xiaoqing

AU - Beesley, Jonathan

AU - Rookus, Matti A.

AU - Verhoef, Senno

AU - Tilanus-Linthorst, Madeleine A.

AU - Vreeswijk, Maaike P.

AU - Asperen, Christi J.

AU - Bodmer, Danielle

AU - Ausems, Margreet G.E.M.

AU - van Os, Theo A.

AU - Blok, Marinus J.

AU - Meijers-Heijboer, Hanne E.J.

AU - Hogervorst, Frans B.L.

AU - Goldgar, David E.

AU - Buys, Saundra

AU - John, Esther M.

AU - Miron, Alexander

AU - Southey, Melissa

AU - Daly, Mary B.

AU - Harbst, Katja

AU - Borg, Åke

AU - Rantala, Johanna

AU - Barbany-Bustinza, Gisela

AU - Ehrencrona, Hans

AU - Stenmark-Askmalm, Marie

AU - Kaufman, Bella

AU - Laitman, Yael

AU - Milgrom, Roni

AU - Friedman, Eitan

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Rebbeck, Timothy R.

AU - Johannsson, Oskar T.

AU - Couch, Fergus J.

AU - Wang, Xianshu

AU - Fredericksen, Zachary

AU - Cuadras, Daniel

AU - Moreno, Víctor

AU - Pientka, Friederike K.

AU - Depping, Reinhard

AU - Caldés, Trinidad

AU - Osorio, Ana

AU - Benítez, Javier

AU - Bueren, Juan

AU - Heikkinen, Tuomas

AU - Nevanlinna, Heli

AU - Hamann, Ute

AU - Torres, Diana

AU - Caligo, Maria A.

AU - Godwin, Andrew K.

AU - Imyanitov, Evgeny N.

AU - Janavicius, Ramunas

AU - Sinilnikova, Olga M.

AU - Stoppa-Lyonnet, Dominique

AU - Mazoyer, Sylvie

AU - Verny-Pierre, Carole

AU - Castera, Laurent

AU - De Pauw, Antoine

AU - Bignon, Yves Jean

AU - Uhrhammer, Nancy

AU - Peyrat, Jean Philippe

AU - Vennin, Philippe

AU - Ferrer, Sandra F.

AU - Collonge-Rame, Marie Agnès

AU - Mortemousque, Isabelle

AU - McGuffog, Lesley

AU - Chenevix-Trench, Georgia

AU - Pereira-Smith, Olivia M.

AU - Antoniou, Antonis C.

AU - Cerón, Julián

AU - Tominaga, Kaoru

AU - Surrallés, Jordi

AU - Pujana, Miguel A.

N1 - Funding Information: The authors thank Dr Andre Nussenzweig, Dr Laura Tusell and Dr Anton Gartner for providing Atm-deficient MEFs, anti-TRF2 and anti-RAD-51/RPA-1 antibodies, respectively. They also wish to thank all study participants, clinicians and centers for their valuable contribution, and the CGEMS initiative for making their genome-wide association study results available. The CIMBA data management is supported by Cancer Research - UK. Funding support is further detailed in Additional file 14.

PY - 2011/4/5

Y1 - 2011/4/5

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 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=84860405722&partnerID=8YFLogxK

U2 - 10.1186/bcr2862

DO - 10.1186/bcr2862

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 21466675

AN - SCOPUS:84860405722

SN - 1465-5411

VL - 13

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 2

M1 - R40

ER -

Exploring the link between MORF4L1 and risk of breast cancer

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UN SDGs

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