Transcriptional Activation of Tumor Suppressor p73 is Modulated by MCL1 Through a Novel Protein Interaction

Precise regulation of apoptosis and cellular response to DNA damage are central to the development of multi‐cellular organisms. In eukaryotes, the BCL2 family of pro‐ and anti‐apoptotic proteins mediate multiple pro‐survival and stress signals to regulate mitochondrial membrane integrity and ultimately apoptosis. Likewise, the p53 family of transcription factors activate multiple pro‐death and cellular senescence pathways in response to DNA damage. Recent studies to develop anti‐cancer agents targeting the BCL2 family have demonstrated that one of the anti‐apoptotic proteins, MCL1, is a critical therapeutic target as it has been shown to inhibit apoptosis in response to a variety of chemotherapeutic agents. MCL1 activity centers around the availability of its BH3 binding cleft to form heterodimers with other pro‐apoptotic BCL2 family proteins. In our search for novel agents that could inhibit these interactions, we identified a novel peptide motif, that we call the reverse BH3 (rBH3) motif, that can interact with the BH3 cleft of MCL1. Here, we show that the p53 homolog, p73, contains a rBH3 motif in its tetramerization domain and that this motif mediates a direct protein‐protein interaction between MCL1 and p73. Furthermore, we show that this interaction allows MCL1 to regulate p73 target gene activation. With MCL1 inhibitors now in clinical trials, we are interrogating the impact that pharmacological inhibition of MCL1 has on DNA damage response signaling in cancer cells who rely on p73 for induction of cell cycle arrest and apoptosis. Support or Funding Information NIH grant R01GM117391 to WJP