Abstract
MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.
Highlights
Complex decisions of cell fate occur in response to genomic stress, mutation, nutrient deprivation, and hypoxia
We confirmed that this dose of cisplatin did not induce apoptosis during this time frame using Annexin V/propidium iodide (PI) flow cytometry where we observed no change in the Annexin V/PI+/− cell population that is associated with apoptotic cells (Supplementary Fig. 3) Using this sub-lethal cisplatin treatment, we were able to generate a baseline for changes in the p73 target gene expression relative to an increase in activation of the native isoforms of p73 protein[51] (Fig. 6)
We have reduced this binding to the specific elements that mediate this interaction: the reverse BH3 (rBH3) motif in the tetramerization domain (TD) of p73 (p73TD) and the canonical hydrophobic-binding groove of MCL1
Summary
P73 contains a putative rBH3-motif in the TD Based on our previously published phage display screen that identified the putative reverse BH3 (rBH3) motif and its specific association with MCL111, we sought to determine if rBH3 sequences found in native proteins are able to mediate direct interactions with the Bcl-2 family.
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