DNA damage-induced PARP/ALC1 activation leads to Epithelial-to-Mesenchymal transition stimulating homologous recombination

Abstract

AbstractEpithelial-to-mesenchymal transition (EMT) allows cancer cells to metastasize while acquiring resistance to apoptosis and to chemotherapeutic agents with significant implications in patients’ prognosis and survival. Despite its clinical relevance, the mechanisms initiating EMT during cancer progression remain poorly understood. We demonstrate that DNA damage triggers EMT by activating PARP and the PARP-dependent chromatin remodeler ALC1 (CHD1L). We show that this activation directly facilitates the access to chromatin of EMT transcriptional factors (TFs) which then initiate cell reprogramming. We also show that EMT-TFs bind to the RAD51 promoter to stimulate its expression and to promote DNA repair by recombination. Importantly, a clinically relevant PARP inhibitor totally reversed or prevented EMT in response to DNA damage while resensitizing tumor cells to other genotoxic agents. Overall, our observations shed light on the intricate relationship between EMT, DNA damage response and PARP inhibitors, providing valuable insights for future therapeutic strategies in cancer treatment.