Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC
Open accessAbstract
MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved "MYC box IIIb" motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ∼80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors.
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The WBM site is well-suited for developing small molecule inhibitors of Myc-WDR5 PPI.
“Hence, it is well-suited for developing small molecule inhibitors of Myc-WDR5 PPI.427”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [427]
Myc generally binds to the WBM site of WDR5, which has a distinct structural feature conserved in Myc proteins.
“Myc generally binds to the WBM site of WDR5, which has a distinct structural feature conserved in Myc proteins.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [427]
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“These boxes have been reported to interact with additional effectors, including CREB-binding p300/CBP transcriptional co-activators, and WDR5 (WD repeat-containing protein 5), which stabilizes Myc interactions with chromatin to promote target gene recognition and Myc-driven tumorigenesis [49].”
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- Authors
- Thomas, L. R., Wang, Q., Grieb, B. C., Phan, J., Foshage, A. M., Sun, Q., Olejniczak, E. T., Clark, T., Dey, S., Lorey, S., Alicie, B., Howard, G. C., Cawthon, B., Ess, K. C., Eischen, C. M., Zhao, Z., Fesik, S. W., & Tansey, W. P.
- Affiliations
- Vanderbilt University (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Tansey, William P.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 58
- Issue
- 3
- Pages
- 440-452
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4427524
- OpenAlex
- W1848866248
- Cited by
- 310
- References
- 39
- Citations by year
- 2026: 24 · 2025: 26 · 2024: 55 · 2023: 38 · 2022: 25 · 2021: 33 · 2020: 23 · 2019: 23 · 2018: 21 · 2017: 20 · 2016: 11 · 2015: 11
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Edward P. Evans Foundation
- Evans Medical Foundation
- National Institutes of Health (1s10od023680-01, DP1OD006933, UL1TR000445)
- National Institute on Aging (F30AG039164)
- National Cancer Institute (CA68485, R01CA148950, P50CA098131, P30CA068485)
- National Institute of General Medical Sciences (T32GM008554, T32GM007347)
- National Institute of Neurological Disorders and Stroke (R01NS078289)
- U.S. National Library of Medicine (R01LM011177)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- c-Myc, WDR5, chromatin recruitment, transcriptional activation, Max, carcinogenesis, induced pluripotent stem cells, anticancer drug targets, protein-protein interaction
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Chromatin, Fluorescence Polarization, Humans, Mice, Nude, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Proteins, Proto-Oncogene Proteins c-myc, Anisotropy, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Two-Hybrid System Techniques, Amino Acid Motifs, NIH 3T3 Cells, Intracellular Signaling Peptides and Proteins, Mice, HEK293 Cells, Carcinogenesis
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