The BRCA2 R2645G variant increases DNA binding and induces hyper-recombination.

Dec 25, 2023

Experts: Lucia Alvaro-Aranda,Ambre Petitalot,Yasmina Djeghmoum,Davide Panigada,Jenny Kaur Singh,Åsa Ehlén,Domagoj Vugic,Charlotte Martin,Simona Miron,Aida Contreras-Perez,Naima Nhiri,Virginie Boucherit,Philippe Lafitte,Isaac Dumoulin,Etienne Rouleau,Eric Jacquet,Lidia Feliubadaló,Jesús Del Valle,Dominique Stoppa-Lyonnet,Sophie Zinn-Justin,Conxi Lázaro,Sandrine M Caputo,Aura Carreira

BRCA2 tumor suppressor protein ensures genome integrity by mediating DNA repair via homologous recombination (HR). This function is executed in part by its canonical DNA binding domain located at the C-terminus (BRCA2CTD), the only folded domain of the protein. Most germline pathogenic missense variants are located in this highly conserved region which binds to single-stranded DNA (ssDNA) and to the acidic protein DSS1. These interactions are essential for the HR function of BRCA2. Here, we report that the variant R2645G, identified in breast cancer and located at the DSS1 interface, unexpectedly increases the ssDNA binding activity of BRCA2CTDin vitro. Human cells expressing this variant display a hyper-recombination phenotype, chromosomal instability in the form of chromatid gaps when exposed to DNA damage, and increased PARP inhibitor sensitivity. In mouse embryonic stem cells (mES), this variant alters viability and confers sensitivity to cisplatin and Mitomycin C. These results suggest that BRCA2 interaction with ssDNA needs to be tightly regulated to limit HR and prevent chromosomal instability and we propose that this control mechanism involves DSS1. Given that several missense variants located within this region have been identified in breast cancer patients, these findings might have clinical implications for carriers.
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

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ABOUT THE EXPERTS

Lucia Alvaro-Aranda,Ambre Petitalot,Yasmina Djeghmoum,Davide Panigada,Jenny Kaur Singh,Åsa Ehlén,Domagoj Vugic,Charlotte Martin,Simona Miron,Aida Contreras-Perez,Naima Nhiri,Virginie Boucherit,Philippe Lafitte,Isaac Dumoulin,Etienne Rouleau,Eric Jacquet,Lidia Feliubadaló,Jesús Del Valle,Dominique Stoppa-Lyonnet,Sophie Zinn-Justin,Conxi Lázaro,Sandrine M Caputo,Aura Carreira

Lucia Alvaro-Aranda

Genome Instability and Cancer Predisposition Laboratory, Centro de Biologia Molecular Severo Ochoa (CBMSO), CSIC-UAM, Madrid 28049, Spain.

Ambre Petitalot

Department of Genetics, Institut Curie, Paris 75005, France.

PSL Research University, Paris 75005, France.

Yasmina Djeghmoum

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Davide Panigada

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Jenny Kaur Singh

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Åsa Ehlén

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Domagoj Vugic

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Charlotte Martin

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Simona Miron

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Paris-Saclay University, 91190 Gif-sur-Yvette, France.

Aida Contreras-Perez

Genome Instability and Cancer Predisposition Laboratory, Centro de Biologia Molecular Severo Ochoa (CBMSO), CSIC-UAM, Madrid 28049, Spain.

Naima Nhiri

Institut de Chimie des Substances Naturelles, Paris-Saclay University, CNRS, 91190 Gif-sur-Yvette, France.

Virginie Boucherit

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Philippe Lafitte

Department of Genetics, Institut Curie, Paris 75005, France.

PSL Research University, Paris 75005, France.

Isaac Dumoulin

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.

Etienne Rouleau

Department of Genetics, Institut Curie, Paris 75005, France.

PSL Research University, Paris 75005, France.

Eric Jacquet

Institut de Chimie des Substances Naturelles, Paris-Saclay University, CNRS, 91190 Gif-sur-Yvette, France.

Lidia Feliubadaló

Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain.

Ciber Oncología (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.

Jesús Del Valle

Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain.

Ciber Oncología (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.

Dominique Stoppa-Lyonnet

Department of Genetics, Institut Curie, Paris 75005, France.

Paris-Cité University, Paris, France.

INSERM U830, Institut Curie, Paris 75005, France.

Sophie Zinn-Justin

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Paris-Saclay University, 91190 Gif-sur-Yvette, France.

Conxi Lázaro

Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain.

Ciber Oncología (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.

Sandrine M Caputo

Department of Genetics, Institut Curie, Paris 75005, France.

PSL Research University, Paris 75005, France.

Aura Carreira

Genome Instability and Cancer Predisposition Laboratory, Centro de Biologia Molecular Severo Ochoa (CBMSO), CSIC-UAM, Madrid 28049, Spain.

Institut Curie, PSL Research University, CNRS, UMR3348, F-91405 Orsay, France.

Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France.