REV1-PolĪ¶ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps
Abstract
BRCA1/2 mutant tumor cells display a heightened mutation burden, the etiology which remains unclear. Here, we are convinced that these cells accumulate ssDNA gaps and spontaneous mutations during unperturbed DNA replication because of repriming through the DNA primase-polymerase PRIMPOL. Gap accumulation necessitates the DNA glycosylase SMUG1 and it is exacerbated by depletion from the translesion synthesis (TLS) factor RAD18 or inhibition from the error-prone TLS polymerase complex REV1-Pol? through the small molecule JH-RE-06. JH-RE-06 management of BRCA1/2-deficient cells leads to reduced mutation rates and PRIMPOL- and SMUG1-dependent lack of viability. Through cellular and animal studies, we show JH-RE-06 is preferentially toxic toward HR-deficient cancer cells. In addition, JH-RE-06 remains effective toward PARP inhibitor (PARPi)-resistant BRCA1 mutant cells and displays additive toxicity with crosslinking agents or PARPi. With each other, these studies identify a safety and mutagenic role for REV1-Pol? JH-RE-06 in BRCA1/2 mutant cells and supply the explanation for implementing REV1-Pol? inhibitors to deal with BRCA1/2 mutant tumors.