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

Violette Azzoni (1, 2) , Julien Wicinski (1, 2) , Manon Macario (1, 2) , Martin Castagné (1, 2) , Pascal Finetti (1, 2) , Katerina Ambrosova (1, 2) , Célia Rouault (1, 2) , Arnaud Sergé (1, 2) , Anne Farina (1, 2) , Emilie Agavnian (2, 1) , Sergiu Coslet (2, 1) , Emmanuelle Josselin (1, 2) , Arnaud Guille (2, 1) , José Adelaide (2, 1) , Emmanouil Zacharioudakis (3) , Rémy Castellano (1, 2) , F. Bertucci (1, 2) , Daniel Birnbaum (1, 2) , Raphael Rodriguez (3) , Emmanuelle Charafe-Jauffret (1, 2, 1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 Institut Paoli-Calmettes
3 Centre de recherche de l'Institut Curie [Paris]

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.

Domains: Life Sciences [q-bio]; Cancer

Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, et al.. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells. Cell Death and Disease, 2022, 13 (2), pp.96. ⟨10.1038/s41419-022-04538-w⟩. ⟨hal-03623505⟩