A Noncanonical Role of MCL-1 in Cell Cycle Progression

Myeloid cell leukemia 1 (MCL-1) is an anti-apoptotic BCL-2 family protein implicated in the development, maintenance, and chemoresistance of human cancer. MCL-1 is one of the most frequently amplified genes across a broad range of malignancies, yet the mechanistic basis for its oncogenic supremacy – relative to its anti-apoptotic homologs – remains unknown. Distin- guishing features of MCL-1 include its large size, owing to its unique N-terminal extension, and the profound pathophysiological consequences that manifest upon genetic deletion, including embryonic lethality. These findings suggest that MCL-1 may have biological functions that ex- tend beyond canonical anti-apoptotic activity, which involves trapping the BH3 death domains of pro-apoptotic members to protect mitochondrial integrity. Here, we uncovered a novel role for MCL-1 in maintaining DNA integrity aand regulating cell cycle progression. We find that genetic deletion and pharmacologic inhibition of MCL-1 impair cellular proliferation and in- duce DNA damage, extending the mechanistic implications of targeting MCL-1 in cancer. In conducting our analyses in leukemia cells that lack BAX and BAK, we confirm that this novel functionality is independent from MCL-1’s role in regulating mitochondrial apoptosis. Taken together, our findings not only broaden the potential utility of inhibiting MCL-1 in cancer by both suppressing proliferation and inducing apoptosis, but also identify therapeutic window consid- erations given the attendant risk of DNA damage to normal tissues.