MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

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.

The multiple mechanisms of MCL1 in the regulation of cell fate

“…Upon activation, the p53 family promotes the upregulation of target genes involved in DDR, halting the cell cycle, and precisely regulating apoptotic protein expression 85 . Interestingly, p63 and p73 contain a unique BH3-like sequence that specifically binds to the canonical BH3-binding cleft of MCL1 86 , 87 . The MCL1–p73 interaction inhibits the p73 DNA-binding capacity and transcriptional activation of DDR target genes 86 .…”

“…Interestingly, p63 and p73 contain a unique BH3-like sequence that specifically binds to the canonical BH3-binding cleft of MCL1 86 , 87 . The MCL1–p73 interaction inhibits the p73 DNA-binding capacity and transcriptional activation of DDR target genes 86 . Under normal circumstances, this mechanism could slow the induction of apoptotic target genes, such as BH3-only proteins NOXA and PUMA, to act as a time management sensor for repair before committing to the cell to apoptosis.…”

“…Furthermore, under malignant conditions in which MCL1 is upregulated, the inhibition of MCL1 on p73 adds an additional layer of resistance on p73 activation. Specific inhibition of MCL1 using BH3-mimetic A-1210477 induces p73, which promotes cell cycle arrest, apoptosis, and DDR target gene expression, suggesting that MCL1 inhibition may reactivate p73 for more effective therapeutic response to platinum-based therapeutics 86 . This study provides yet another targeted protein interaction in the DDR pathway that could be exploited for combination therapy in cancer treatment regimens to activate DDR at the transcriptional level.…”

“…Another new avenue of research in MCL1 biology encompasses a novel class of MCL1-binding proteins that contain a reverse BH3 (rBH3) motif, which specifically bind to MCL1 over the other anti-apoptotic Bcl-2 family members 87 . Recently, two rBH3-mediated interactions have been identified and characterized between cell cycle regulator p18 63 and tumor-suppressor p73 86 . Notably, while these proteins interact with MCL1 through the consensus BH3 pocket, they do not appear to impact MCL1s regulation of apoptosis at the OMM 63 , 86 .…”

“…Recently, two rBH3-mediated interactions have been identified and characterized between cell cycle regulator p18 63 and tumor-suppressor p73 86 . Notably, while these proteins interact with MCL1 through the consensus BH3 pocket, they do not appear to impact MCL1s regulation of apoptosis at the OMM 63 , 86 . Instead, these novel protein interactions appear to impact their endogenous function in cell cycle regulation and transcriptional activation, respectively.…”