RNF25 provides tolerance towards chemotherapeutic mRNA damage

Many chemotherapeutic agents damage DNA, which is believed to mediate their therapeutic efficacy. However, most of these agents act pleiotropically and also damage RNA, raising questions about the contribution of RNA damage to therapeutic outcomes and whether cells possess factors that protect them from chemotherapeutic RNA damage. In this project, we compare the cellular response to azacytidine (azaC) and decitabine (azadC), two nucleoside analogues that are used to treat acute myeloid leukemia (AML). We uncovered that 5azaC induces RNA damage and triggers cell death through the integrated stress response, which is mediated by GCN1 and GCN2. We also identified the ubiquitin E3 ligases RNF25 as a specific resistance factor to 5azaC treatment. Combining ubiquitylome and phospho-proteome, we explore the underlying cellular signalling associated with 5azaC sensitivity and resistance