MCL1 may not mediate chemoresistance in cancer cells

The anti-apoptotic B-cell lymphoma 2 (BCL2) family member myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers and has been linked to chemoresistance. Unlike other BCL2 family members, MCL1 displays both well-defined mitochondrial anti-apoptotic activities and emerging nuclear functions. Prior reports suggest that MCL1 enters the nucleus during chemotherapy treatment and confers chemoresistance by influencing cell cycle progression and DNA repair. These nuclear roles of MCL1, however, remain poorly characterized. Using a newly validated monoclonal antibody across several cell lines and treatments, we find no evidence that MCL1 enhances chemoresistance or preferentially accumulates in the nucleus after drug exposure. Indeed, bulk RNA sequencing data suggest that MCL1 loss dampens, rather than potentiates, transcriptional responses to DNA-damaging chemotherapy. Proximity biotinylation experiments identified novel nuclear MCL1 interactors but did not recover previously reported DNA repair or cell cycle partners. Thus, while MCL1 does reach the nucleus and interact with nuclear proteins, our data do not support a role for MCL1 in chemoresistance. Further work is needed to clarify the functional significance of nuclear MCL1.