DNA damage-induced EMT controlled by the PARP dependent chromatin remodeler ALC1 promotes DNA repair efficiency through RAD51 in tumor cells
Significance Statement
EMT is a key phenomenon that confers to cancer cells the ability to metastasize. What triggers EMT is not fully understood.
The authors show that DNA damage induces EMT in cancer cells in a PARP1/ALC1-dependent manner, and that, in turn, EMT improves the capacity of cancer cells to repair DNA damage, through homologous recombination, rendering cells more resistant to chemotherapeutic drugs.
These findings suggest that PARP inhibitors may prevent or reverse EMT while restoring drug sensitivity.
Abstract
Epithelial-to-mesenchymal transition (EMT) allows cancer cells to metastasize while acquiring resistance to apoptosis and chemotherapeutic agents with significant implications for 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 and that activation of poly (ADP-ribose) polymerase (PARP) and the PARP-dependent chromatin remodeler ALC1 (CHD1L) was required for this response. Our results suggest that this activation directly facilitates access to the 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 homologous recombination. Importantly, a clinically relevant PARP inhibitor 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 potential insights for in cancer therapeutics.
