PLK1 and NOTCH1 at the interface of DNA Damage Checkpoint and tolerance to genotoxic stress

Notch signalling plays a complex role in carcinogenesis and its signaling pathway has both tumor-suppressor and oncogenic components. We have shown that deregulation of NOTCH1 signalling is a crucial mechanism involved in Arsenic-induced keratinocyte transformation. We have used the Arsenic-induced transformation model to probe cellular and molecular mechanisms that control the duality of NOTCH1 signaling in malignant transformation. Here, to identify regulators that might control this dual activity of NOTCH1, we screened a chemical library targeting kinases and identified Polo-Like kinase 1 (PLK1) as one of the kinases involved in Arsenite-induced NOTCH1 downmodulation. We show that this critical correlation represents an important regulatory mechanism of NOTCH1 expression in the G2 phase of the cell cycle and in response to DNA damage in G2. Our results suggest that genotoxic stress causes a PLK1-dependent signalling response that antagonizes the involvement of NOTCH1 in the DNA damage checkpoint. Although, its precise contribution to the oncogenic phenotype of epithelial cancer remain unclear, we provide evidence that Notch signaling is altered but not abolished in SCC cells. Thus, it is also important to recognize that even in a single type of tumor, there is plasticity in Notch function and the dual role of NOTCH in cancer biology is undoubtedly complex and tumor type-independent.