Morales-Valencia, J. | Search bioRxiv

bioRxiv2022

The chromatin associated Sin3B is a critical regulator of DNA damage repair through the engagement of the Non-Homologous End Joining.

Transcription and DNA damage repair act in a coordinated manner. The scaffolding protein Sin3B serves as a transcriptional corepressor of hundreds of cell-cycle-related genes. However, the role of Sin3B during the DNA damage response still remains unknown. Here, we show that Sin3B depletion delays the resolution of DNA double-strand breaks (DSBs) and sensitizes cells to diverse DNA-damaging agents, including cisplatin and doxorubicin. Furthermore, Sin3B is rapidly recruited to DNA damage sites and interacts with other DDR proteins. Mechanistically, Sin3B promotes non-homologous end joining DNA repair by directing the accumulation of MDC1 at DBSs. Altogether, our findings impute an unexpected function for the transcriptional co-repressor Sin3B as a gatekeeper of genomic integrity, and point to the inhibition of the Sin3B chromatin modifying complex as a novel therapeutic vulnerability in cancer cells.

cancer biology↗

bioRxiv2022

Lipocalin 2 upregulation mediates the detrimental effects of therapy-induced senescence in breast cancer cells.

The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin 2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.

cancer biology↗