Targeting MCL-1 Causes DNA Damage and Cell Cycle Arrest Independent from Apoptosis Induction

MCL-1 is a high-priority target due to its dominant role in the pathogenesis and chemoresistance of cancer, yet clinical trials of MCL-1 inhibitors are revealing toxic side-effects. MCL-1 biology is complex, extending beyond apoptotic regulation and confounded by its multiple isoforms, domains of unknown structure and function, and challenges in distinguishing noncanonical activities from the apoptotic response. We find that, in the presence or absence of an intact mitochondrial apoptotic pathway, genetic deletion or pharmacologic targeting of MCL-1 triggers DNA damage and cell cycle arrest. Indeed, the cancer cell susceptibility profile of MCL-1 inhibitors better matches that of anti-proliferative than pro-apoptotic drugs, expanding their potential therapeutic applications, including synergistic combinations, but heightening therapeutic window concerns. Proteomic profiling across cell cycle stages provides a resource for mechanistic dissection and revealed MCM among other MCL-1-interacting nuclear protein complexes that link MCL-1 to the regulation of DNA integrity and cell cycle progression.