BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Violette Azzoni; Julien Wicinski; Manon Macario; Martin Castagné; Pascal Finetti; Katerina Ambrosova; Célia D. Rouault; Arnaud Sergé; Anne Farina; Emilie Agavnian; Sergiu Coslet; Emmanuelle Josselin; Arnaud Guille; José Adelaide; Emmanouil Zacharioudakis; Rémy Castellano; Francois Bertucci; Daniel Birnbaum; Raphael Rodriguez; Emmanuelle Charafe-Jauffret; Christophe Ginestier

doi:10.1038/s41419-022-04538-w

BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, Katerina Ambrosova, Célia D. Rouault, Arnaud Sergé, Anne Farina, Emilie Agavnian, Sergiu Coslet, Emmanuelle Josselin, Arnaud Guille, José Adelaide, Emmanouil Zacharioudakis, Rémy Castellano, Francois Bertucci, Daniel Birnbaum, Raphael Rodriguez, Emmanuelle Charafe-JauffretChristophe Ginestier

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

10 Scopus citations

Abstract

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

Original language	English (US)
Article number	96
Journal	Cell Death and Disease
Volume	13
Issue number	2
DOIs	https://doi.org/10.1038/s41419-022-04538-w
State	Published - Feb 2022
Externally published	Yes

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

UN SDGs

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

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10.1038/s41419-022-04538-w

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Azzoni, V., Wicinski, J., Macario, M., Castagné, M., Finetti, P., Ambrosova, K., Rouault, C. D., Sergé, A., Farina, A., Agavnian, E., Coslet, S., Josselin, E., Guille, A., Adelaide, J., Zacharioudakis, E., Castellano, R., Bertucci, F., Birnbaum, D., Rodriguez, R., ... Ginestier, C. (2022). BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells. Cell Death and Disease, 13(2), Article 96. https://doi.org/10.1038/s41419-022-04538-w

Azzoni, V, Wicinski, J, Macario, M, Castagné, M, Finetti, P, Ambrosova, K, Rouault, CD, Sergé, A, Farina, A, Agavnian, E, Coslet, S, Josselin, E, Guille, A, Adelaide, J, Zacharioudakis, E, Castellano, R, Bertucci, F, Birnbaum, D, Rodriguez, R, Charafe-Jauffret, E & Ginestier, C 2022, 'BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells', Cell Death and Disease, vol. 13, no. 2, 96. https://doi.org/10.1038/s41419-022-04538-w

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title = "BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells",

abstract = "Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells{\textquoteright} (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.",

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doi = "10.1038/s41419-022-04538-w",

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AU - Azzoni, Violette

AU - Wicinski, Julien

AU - Macario, Manon

AU - Castagné, Martin

AU - Finetti, Pascal

AU - Ambrosova, Katerina

AU - Rouault, Célia D.

AU - Sergé, Arnaud

AU - Farina, Anne

AU - Agavnian, Emilie

AU - Coslet, Sergiu

AU - Josselin, Emmanuelle

AU - Guille, Arnaud

AU - Adelaide, José

AU - Zacharioudakis, Emmanouil

AU - Castellano, Rémy

AU - Bertucci, Francois

AU - Birnbaum, Daniel

AU - Rodriguez, Raphael

AU - Charafe-Jauffret, Emmanuelle

AU - Ginestier, Christophe

PY - 2022/2

Y1 - 2022/2

N2 - Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

AB - Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

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BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Abstract

ASJC Scopus subject areas

UN SDGs

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