REV1 inhibition elicits differential response to cancer therapy

Abstract

Translesion synthesis (TLS) is a DNA damage tolerance mechanism that acts to bypass lesions at stalled replication forks. Recently, TLS has been implicated in cancer resistance to chemotherapy as it allows replication of DNA over genotoxic insults to promote cancer cell proliferation. Targeting the central scaffolding protein in this process, REV1, has emerged as a potential method for sensitizing cancer cells to chemotherapy. Most notably, REV1 inhibition sensitizes cancer cells to cisplatin treatment. We further investigated whether REV1 inhibition could sensitize cancer cells to ionizing radiation (IR). Here, we report that REV1 inhibition confers radioresistance and triggers the induction of autophagy which is modulated by different DNA-damaging agents. This radioresistant phenotype is observed in vitro and in vivo. These findings present REV1 and TLS as modulators of response to various types of DNA damaging therapies and warrant further study to determine the therapeutic potential of REV1 inhibition