Significance Mutagenic translesion synthesis (TLS) increases cell survival after DNA damage by bypassing lesions that normally block DNA replication but introduces mutations. In cancer cells, REV1/POLζ-dependent mutagenic TLS can contribute to intrinsic chemoresistance, while the mutations it introduces can underlie acquired chemoresistance. Interfering with this TLS pathway genetically or with the small molecule inhibitor JH-RE-06 has been shown to improve cisplatin chemotherapy by suppressing tumor growth and enhancing survival in mouse xenograft tumor models. Cisplatin chemotherapy commonly exerts its antitumor effects via DNA damage-mediated apoptosis. However, in two mouse xenograft models and four mammalian cell lines, the JH-RE-06 unexpectedly profoundly alters the biological response to cisplatin. Apoptosis is suppressed and surprisingly numerous hallmarks of senescence are induced prior to cell death.