Cellular redox sensor HSCARG negatively regulates the translesion synthesis pathway and exacerbates mammary tumorigenesis

The TLS pathway plays a vital role in maintaining genome integrity during DNA replication. Here we describe a previously unknown TLS regulatory mechanism mediated by HSCARG, a cellular redox sensor. HSCARG enhances the interaction between PCNA and USP1 and thus inhibits PCNA ubiquitination, which further impairs the recruitment of POLH and promotes the generation of DSBs. Consequently, the up-regulation of HSCARG exacerbates mammary tumorigenesis. Importantly, the cellular redox state regulates HSCARG dimerization and subcellular localization and influences the efficiency of HSCARG in regulating the TLS pathway. Our studies discover a regulator of the TLS pathway and identify a crosstalk between the cellular redox status and the DNA damage response.