bims-midomi Biomed News
on MDM2 and mitochondria
Issue of 2026–08–09
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. BRCA1-derived peptide constructs exhibit sequence-dependent features compatible with modulation of the p53-MDM2 axis.
  2. MDM2 binds and suppresses RNA polymerase III to restrain the innate immune response to cytosolic DNA.
  1. Mol Biol Rep. 2026 Aug 06. pii: 1349. [Epub ahead of print]53(1):
    BRCA1-derived peptide constructs exhibit sequence-dependent features compatible with modulation of the p53-MDM2 axis.
    Serap Pektaş.
       BACKGROUND: The p53-MDM2 interaction is a central regulator of p53 protein stability and an important target for restoration of p53 function. Most peptide-based approaches targeting this interaction are derived from the p53 transactivation domain and preserve the canonical F-W-L hydrophobic motif. Here, BRCA1-derived peptide constructs were used to investigate how hydrophobic motif composition and sequence context influence peptide compatibility with the MDM2 binding interface.
    METHODS AND RESULTS: Short peptide segments derived from BRCA1 phosphorylation regions were engineered to contain hydrophobic anchor residues corresponding to the p53-MDM2 interaction while permitting variation in motif composition, including non-canonical F-W-F configurations. Peptides were evaluated using molecular docking, molecular dynamics simulations, and cellular assays based on EGFP-linker-peptide fusion constructs in HEK293T cells. Several BRCA1-derived peptides were associated with increased p53 protein levels in this system, with pBR3 and pBR4 showing the highest mean levels. Notably, both peptides contained non-canonical F-W-F motifs and showed greater activity than several peptides with comparable docking scores. Molecular dynamics and residue-level contact occupancy analyses were consistent with sustained association of the peptides with the MDM2 binding cleft despite interaction patterns that differed from those of reference p53-derived inhibitors.
    CONCLUSIONS: These findings indicate that modulation of the p53-MDM2 axis is influenced by both hydrophobic motif composition and sequence context. The results further suggest that alternative hydrophobic residue arrangements can support compatibility with the MDM2 binding interface, providing a framework for exploring non-p53-derived peptide architectures targeting the p53-MDM2 interaction.
    Keywords:  BRCA1–derived peptides; Hydrophobic motifs; MDM2; Molecular dynamics simulation; Protein–protein interaction; Sequence-dependent activity; p53; p53–MDM2 axis
    DOI:  https://doi.org/10.1007/s11033-026-12535-x
  2. Cell Death Differ. 2026 Aug 06.
    MDM2 binds and suppresses RNA polymerase III to restrain the innate immune response to cytosolic DNA.
    Sabrina Weber, Valentina Manzini, Helene Dietrich, Hannah Schotte, Sergei Moshkovskii, Philipp Hackert, Emre Taylan Duman, Nhu Quang Vu, Evangelos Prokakis, Gabriela Salinas, Christof Lenz, Henning Urlaub, Katherine E Bohnsack, Markus T Bohnsack, Matthias Dobbelstein.
      The oncoprotein MDM2 is widely recognized as the principal negative regulator of p53, thereby controlling the expression of numerous RNA polymerase II (Pol II)-dependent genes involved in cell cycle arrest and apoptosis. Beyond this canonical role, MDM2 also engages in transcriptional regulation independently of p53, for instance through interactions with polycomb repressor complexes. Here, we identify RNA polymerase III (Pol III) as an additional target of MDM2 function. Using two complementary chemical tools-a small-molecule MDM2 antagonist (MI-1061) that releases p53 and augments MDM2 expression, and a PROTAC degrader (MD-224) that simultaneously activates p53 and promotes MDM2 ubiquitination and proteasomal destruction-we dissected the role of MDM2 in cells with amplified MDM2. Elevated MDM2 suppressed the transcription of Pol III-dependent genes encoding tRNA or 5S ribosomal RNA. Mechanistically, we found the aminoterminal domain of MDM2 associated with the catalytic subunit of Pol III, revealing a molecular link between MDM2 and the Pol III machinery. Because Pol III also acts as a cytosolic DNA sensor that converts DNA into double-stranded RNA to trigger RIG-I-TBK1-IRF3-dependent signaling, we asked whether MDM2 modulates this pathway. Indeed, enhanced MDM2 expression markedly attenuated the induction of innate immunity genes such as CXCL10, OAS1, and MX1 following transfection with poly(dA:dT). Similarly, DNA damage induced by a radiomimetic agent activated Pol III-dependent innate signaling, and this was again blunted by high MDM2 levels, resulting in enhanced cell survival. Taken together, our findings establish MDM2 as a previously unrecognized suppressor of Pol III-dependent transcription in response to cytosolic DNA. This expands the repertoire of MDM2 functions beyond repression of p53 and Pol II activity, positioning MDM2 as a broad regulator of transcription and innate immunity.
    DOI:  https://doi.org/10.1038/s41418-026-01834-2
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