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12. LUMIERE on the FETUS (FETUS)

Author

LUMIERE Fondation ( fondation-lumiere.org) under the aegis of Fondation de France and University of Paris 5 - Rene Descartes

Published
2023

15. LUMIERE on the PLACENTA

Author

LUMIERE Fondation ( fondation-lumiere.org) under the aegis of Fondation de France and University of Paris 5 - Rene Descartes

Published
2022

19. CRESPI - Respiratory Health of Children in Daycare (CRESPI)

Author

Centre Scientifique et Technique du Bâtiment, EPICONCEPT, Ecole des Hautes Etudes en Santé Publique, ANSES, ADEME, National Research Agency, France, Agence Regionale de Sante d'Ile de France, and Fondation de France

Published
2019

41. Making protected areas effective for biodiversity, climate and food

Author

Helmholtz Association, BiodivERsA, Fondation de France, European Commission, LabEx BASC, Belmont Forum, Agencia Estatal de Investigación (España), Projekt DEAL, Arneth, Almut, Leadley, Paul, Claudet, Joachim, Coll, Marta, Rondinini, Carlo, Rounsevell, Mark D.A., Shin, Yunne-Jai, Alexander, Peter, Fuchs, Richard, Helmholtz Association, BiodivERsA, Fondation de France, European Commission, LabEx BASC, Belmont Forum, Agencia Estatal de Investigación (España), Projekt DEAL, Arneth, Almut, Leadley, Paul, Claudet, Joachim, Coll, Marta, Rondinini, Carlo, Rounsevell, Mark D.A., Shin, Yunne-Jai, Alexander, Peter, and Fuchs, Richard

Abstract

The spatial extent of marine and terrestrial protected areas (PAs) was among the most intensely debated issues prior to the decision about the post-2020 Global Biodiversity Framework (GBF) of the Convention on Biological Diversity. Positive impacts of PAs on habitats, species diversity and abundance are well documented. Yet, biodiversity loss continues unabated despite efforts to protect 17% of land and 10% of the oceans by 2020. This casts doubt on whether extending PAs to 30%, the agreed target in the Kunming-Montreal GBF, will indeed achieve meaningful biodiversity benefits. Critically, the focus on area coverage obscures the importance of PA effectiveness and overlooks concerns about the impact of PAs on other sustainability objectives. We propose a simple means of assessing and visualising the complex relationships between PA area coverage and effectiveness and their effects on biodiversity conservation, nature-based climate mitigation and food production. Our analysis illustrates how achieving a 30% PA global target could be beneficial for biodiversity and climate. It also highlights important caveats: (i) achieving lofty area coverage objectives alone will be of little benefit without concomitant improvements in effectiveness, (ii) trade-offs with food production particularly for high levels of coverage and effectiveness are likely and (iii) important differences in terrestrial and marine systems need to be recognized when setting and implementing PA targets. The CBD's call for a significant increase in PA will need to be accompanied by clear PA effectiveness goals to reduce and revert dangerous anthropogenic impacts on socio-ecological systems and biodiversity

Published
2023

44. Enhanced wild-Type mET Receptor levels in mouse hepatocytes attenuates insulin-mediated signaling

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Fundación Ramón Areces, Instituto de Salud Carlos III, Institut National du Cancer (France), Aix-Marseille Université, Fondation de France, Fondation ARC pour la Recherche sur le Cancer, Rada, Patricia, Lamballe, Fabienne, Cárcer, Guillermo de, Carceller-López, Elena, Hitos, Ana B., Sequera, Celia, Maina, Flavio, Valverde, Ángela M., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Fundación Ramón Areces, Instituto de Salud Carlos III, Institut National du Cancer (France), Aix-Marseille Université, Fondation de France, Fondation ARC pour la Recherche sur le Cancer, Rada, Patricia, Lamballe, Fabienne, Cárcer, Guillermo de, Carceller-López, Elena, Hitos, Ana B., Sequera, Celia, Maina, Flavio, and Valverde, Ángela M.

Abstract

Compelling evidence points to the MET receptor tyrosine kinase as a key player during liver development and regeneration. Recently, a role of MET in the pathophysiology of insulin resistance and obesity is emerging. Herein, we aimed to determine whether MET regulates hepatic insulin sensitivity. To achieve this, mice in which the expression of wild-type MET in hepatocytes is slightly enhanced above endogenous levels (Alb-R26Met mice) were analyzed to document glucose homeostasis, energy balance, and insulin signaling in hepatocytes. We found that Alb-R26Met mice exhibited higher body weight and food intake when compared to R26stopMet control mice. Metabolic analyses revealed that Alb-R26Met mice presented age-related glucose and pyruvate intolerance in comparison to R26stopMet controls. Additionally, in Alb-R26Met mice, high MET levels decreased insulin-induced insulin receptor (IR) and AKT phosphorylation compared to control mice. These results were corroborated in vitro by analyzing IR and AKT phosphorylation in primary mouse hepatocytes from Alb-R26Met and R26stopMet mice upon insulin stimulation. Moreover, co-immunoprecipitation assays revealed MET-IR interaction under both basal and insulin stimulation conditions; this effect was enhanced in Alb-R26Met hepatocytes. Altogether, our results indicate that enhanced MET levels alter hepatic glucose homeostasis, which can be an early event for subsequent liver pathologies.

Published
2022

45. Lipoprotein metabolism in familial hypercholesterolemia

Author

Interreg, Conseil Régional de la Réunion, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fondation pour la Recherche Médicale, Eusko Jaurlaritza, Agence Nationale de la Recherche (France), Fondation de France, Blom, Dirk [0000-0003-3965-5912], Chemello, Kevin, García-Nafría, Javier, Gallo, Antonio, Martín, César, Lambert, Gilles, Blom, Dirk, Interreg, Conseil Régional de la Réunion, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fondation pour la Recherche Médicale, Eusko Jaurlaritza, Agence Nationale de la Recherche (France), Fondation de France, Blom, Dirk [0000-0003-3965-5912], Chemello, Kevin, García-Nafría, Javier, Gallo, Antonio, Martín, César, Lambert, Gilles, and Blom, Dirk

Abstract

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.

Published
2021

46. A Systematic Approach to Assess the Activity and Classification of PCSK9 Variants

Author

Eusko Jaurlaritza, Agence Nationale de la Recherche (France), Fondation de France, Fundación Biofísica Bizkaia, Universidad del País Vasco, European Commission, Interreg, Conseil Régional de la Réunion, Uribe, Kepa B., Chemello, Kevin, Larrea, Asier, Benito-Vicente, Asier, Galicia-García, Unai, Bourane, Steeve, Jaafar, Ali K., Lambert, Gilles, Martín, César, Eusko Jaurlaritza, Agence Nationale de la Recherche (France), Fondation de France, Fundación Biofísica Bizkaia, Universidad del País Vasco, European Commission, Interreg, Conseil Régional de la Réunion, Uribe, Kepa B., Chemello, Kevin, Larrea, Asier, Benito-Vicente, Asier, Galicia-García, Unai, Bourane, Steeve, Jaafar, Ali K., Lambert, Gilles, and Martín, César

Abstract

Gain of function (GOF) mutations of PCSK9 cause autosomal dominant familial hypercholesterolemia as they reduce the abundance of LDL receptor (LDLR) more efficiently than wild-type PCSK9. In contrast, PCSK9 loss of function (LOF) variants are associated with a hypocholesterolemic phenotype. Dozens of PCSK9 variants have been reported, but most remain of unknown significance since their characterization has not been conducted.

Published
2021

47. Anatomy of digital contact tracing: Role of age, transmission setting, adoption, and case detection

Author

Agence Nationale de la Recherche (France), European Commission, Fondation de France, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Moreno López, Jesús A., Arregui García, Beatriz, Bentkowski, Piotr, Bioglio, Livio, Pinotti, Francesco, Boëlle, Pierre-Yves, Barrat, Alain, Colizza, Vittoria, Poletto, Chiara, Agence Nationale de la Recherche (France), European Commission, Fondation de France, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Moreno López, Jesús A., Arregui García, Beatriz, Bentkowski, Piotr, Bioglio, Livio, Pinotti, Francesco, Boëlle, Pierre-Yves, Barrat, Alain, Colizza, Vittoria, and Poletto, Chiara

Abstract

The efficacy of digital contact tracing against coronavirus disease 2019 (COVID-19) epidemic is debated: Smartphone penetration is limited in many countries, with low coverage among the elderly, the most vulnerable to COVID-19. We developed an agent-based model to precise the impact of digital contact tracing and household isolation on COVID-19 transmission. The model, calibrated on French population, integrates demographic, contact and epidemiological information to describe exposure and transmission of COVID-19. We explored realistic levels of case detection, app adoption, population immunity, and transmissibility. Assuming a reproductive ratio R = 2.6 and 50% detection of clinical cases, a ~20% app adoption reduces peak incidence by ~35%. With R = 1.7, >30% app adoption lowers the epidemic to manageable levels. Higher coverage among adults, playing a central role in COVID-19 transmission, yields an indirect benefit for the elderly. These results may inform the inclusion of digital contact tracing within a COVID-19 response plan.

Published
2021

48. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Nyberg, Lars, Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, and Nyberg, Lars

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

49. WDR34, a candidate gene for non-syndromic rod-cone dystrophy

Author

Ministère de l’Enseignement supérieur et de la Recherche (France), Fondation de France, Foundation Fighting Blindness, Fondation Voir et Entendre, Agence Nationale de la Recherche (France), National Eye Institute (US), Région Ile-de-France, Association Française contre les Myopathies, Solaguren-Beascoa, María, Bujakowska, Kinga, Méjécase, Cécile, Emmenegger, Lisa, Orhan, Elise, Neuillé, Marion, Mohand-Saïd, Saddek, Condroyer, Christel, Lancelot, Marie-Elise, Michiels, Christelle, Demontant, Vanessa, Antonio, Aline, Letexier, Mélanie, Saraiva, Jean-Paul, Lonjou, Christine, Carpentier, Wassila, Léveillard, Thierry, Pierce, Eric A., Dollfus, Hélène, Sahel, José-Alain, Bhattacharya, Shom Shanker, Audo, Isabelle, Zeitz, Christina, Ministère de l’Enseignement supérieur et de la Recherche (France), Fondation de France, Foundation Fighting Blindness, Fondation Voir et Entendre, Agence Nationale de la Recherche (France), National Eye Institute (US), Région Ile-de-France, Association Française contre les Myopathies, Solaguren-Beascoa, María, Bujakowska, Kinga, Méjécase, Cécile, Emmenegger, Lisa, Orhan, Elise, Neuillé, Marion, Mohand-Saïd, Saddek, Condroyer, Christel, Lancelot, Marie-Elise, Michiels, Christelle, Demontant, Vanessa, Antonio, Aline, Letexier, Mélanie, Saraiva, Jean-Paul, Lonjou, Christine, Carpentier, Wassila, Léveillard, Thierry, Pierce, Eric A., Dollfus, Hélène, Sahel, José-Alain, Bhattacharya, Shom Shanker, Audo, Isabelle, and Zeitz, Christina

Abstract

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.

Published
2021

50. BRCA2 promotes DNA-RNA hybrid resolution by DDX5 helicase at DNA breaks to facilitate their repair‡

Author

Agence Nationale de la Recherche (France), Institut National du Cancer (France), Ligue Nationale contre le Cancer (France), European Research Council, Ministerio de Economía y Competitividad (España), Fundación Vencer el Cancer, European Commission, Institut Curie, Centre National de la Recherche Scientifique (France), Fondation ARC pour la Recherche sur le Cancer, Ministére de l'Education Nationale de la Recherche et de la Technologie (France), Asociación Española Contra el Cáncer, Ministerio de Economía, Industria y Competitividad (España), Fondation de France, Sessa, Gaetana, Gómez-González, Belén, Silva, Sonia, Pérez-Calero, Carmen, Beaurepere, Romane, Barroso, Sonia, Martineau, Sylvain, Martin, Charlotte, Ehlén, Åsa, Martínez, Juan S., Lombard, Bérangère, Loew, Damarys, Vagner, Stephan, Aguilera, Andrés, Carreira, Aura, Agence Nationale de la Recherche (France), Institut National du Cancer (France), Ligue Nationale contre le Cancer (France), European Research Council, Ministerio de Economía y Competitividad (España), Fundación Vencer el Cancer, European Commission, Institut Curie, Centre National de la Recherche Scientifique (France), Fondation ARC pour la Recherche sur le Cancer, Ministére de l'Education Nationale de la Recherche et de la Technologie (France), Asociación Española Contra el Cáncer, Ministerio de Economía, Industria y Competitividad (España), Fondation de France, Sessa, Gaetana, Gómez-González, Belén, Silva, Sonia, Pérez-Calero, Carmen, Beaurepere, Romane, Barroso, Sonia, Martineau, Sylvain, Martin, Charlotte, Ehlén, Åsa, Martínez, Juan S., Lombard, Bérangère, Loew, Damarys, Vagner, Stephan, Aguilera, Andrés, and Carreira, Aura

Abstract

The BRCA2 tumor suppressor is a DNA double-strand break (DSB) repair factor essential for maintaining genome integrity. BRCA2-deficient cells spontaneously accumulate DNA-RNA hybrids, a known source of genome instability. However, the specific role of BRCA2 on these structures remains poorly understood. Here we identified the DEAD-box RNA helicase DDX5 as a BRCA2-interacting protein. DDX5 associates with DNA-RNA hybrids that form in the vicinity of DSBs, and this association is enhanced by BRCA2. Notably, BRCA2 stimulates the DNA-RNA hybrid-unwinding activity of DDX5 helicase. An impaired BRCA2-DDX5 interaction, as observed in cells expressing the breast cancer variant BRCA2-T207A, reduces the association of DDX5 with DNA-RNA hybrids, decreases the number of RPA foci, and alters the kinetics of appearance of RAD51 foci upon irradiation. Our findings are consistent with DNA-RNA hybrids constituting an impediment for the repair of DSBs by homologous recombination and reveal BRCA2 and DDX5 as active players in their removal.

Published
2021

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