Proposed model of the relationship between UBA1 activity and TAK243 sensitivity.UBA1^M41 missense mutations lead to UBA1b loss and expression of a dysfunctional protein isoform, UBA1c, which is associated with diminished UBA1 activity and a global reduction in polyubiquitination. In this context, reduced UBA1 activity renders UBA1^M41 mutant cells vulnerable to targeted UBA1 inhibition by TAK243. Exogenous expression of UBA1b in UBA1^M41 mutant cells is sufficient to restore UBA1 activity and promote TAK243 resistance.