ABSTRACT
Genome instability mechanisms that characterize cancer initiation and subsequent therapy resistance are still less well understood. Recent evidence suggests that the REV1-dependent translesion synthesis (TLS) is the cornerstone for new mutation formation that primes genome instability, including intrinsic and acquired resistance to therapy. Remarkably, REV1 inhibition also switches the biology of cisplatin-dependent cell death response from apoptosis to senescence, suggesting that REV1 functions beyond a DNA damage polymerase. Furthermore, we discovered two unexpected phenotypes of REV1 TLS polymerase: a) REV1 inhibition triggers autophagy that associated with radioresistance. b) By means of striking preliminary data we show that REV1 inhibition limits SARS-CoV-2 RNA virus propagation, which we recently reported to cause hostcell DNA damage response and telomere instability. These new observations add to the repertoire of REV1- dependent genome instability pathways significant to understanding a wide repertoire of human diseases, including cancer pathogenesis.