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

Hayley Widden1, Aneta Kaczmarczyk1, Ashok Subedi1

  • 1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.

Cell Death & Disease
|November 4, 2020
PubMed

Insights

MCL1 protein directly regulates p73 transcriptional activity via its reverse BH3 motif, impacting DNA damage response and apoptosis. This discovery offers new strategies for combining MCL1 inhibitors with chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Death Pathways

Background:

  • MCL1 is an anti-apoptotic protein crucial for regulating intrinsic apoptosis and chemosensitivity.
  • Targeting MCL1 is a key strategy in anti-cancer drug development, with specific inhibitors in clinical trials.
  • Understanding MCL1's interaction with other proteins is vital for optimizing cancer therapies.

Purpose of the Study:

  • To elucidate the direct role of MCL1 in regulating p73 transcriptional activity.
  • To identify the specific mechanism by which MCL1 controls p73.
  • To provide a basis for combining MCL1 inhibitors with platinum-based chemotherapeutics.

Main Methods:

  • Investigated the interaction between MCL1 and p73.
  • Characterized the role of the reverse BH3 (rBH3) motif in p73.
  • Assessed the impact of MCL1 on p73-mediated transcriptional regulation of target genes.

Main Results:

  • Established a direct role for MCL1 in controlling p73 transcriptional activity.
  • Identified the reverse BH3 (rBH3) motif in p73's tetramerization domain as the mediator of MCL1 interaction.
  • Demonstrated that MCL1 binding restricts p73 assembly on DNA, thereby modulating gene expression.
  • Showed that p73 target genes are involved in DNA damage response, apoptosis, and cell cycle progression.

Conclusions:

  • MCL1 directly regulates p73 transcriptional activity through its rBH3 motif, expanding its known functions beyond cell fate regulation.
  • This novel mechanism of protein-level regulation of p73 by MCL1 provides a foundation for developing combination therapies.
  • The findings support the use of MCL1 inhibitors in conjunction with platinum-based chemotherapeutics for enhanced anti-cancer efficacy.

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