A HECT-domain containing E3 ubiquitin ligase that mediates the polyubiquitination of Mcl-1, named Mule for Mcl-1 ubiquitin ligase E3, is described. Methods and compositions for modulating functional interaction between Mcl-1 and Mule protein and Mcl-1 mediated apoptosis are described. Diagnostic and prognostic methods based on Mule expression in patient cells are also described.