The biologic activity of MYC is largely dependent on binding of WDR5 to the MYC MbIIIb motif.

  • Major finding: The biologic activity of MYC is largely dependent on binding of WDR5 to the MYC MbIIIb motif.

  • Concept: Disrupting the MYC–WDR5 interaction broadly reduces MYC chromatin binding and blocks tumor growth.

  • Impact: Small molecules that target the MYC–WDR5 interface may be effective in MYC-dependent cancers.

Binding of MYC to DNA is dependent on its heterodimerization with MAX, but other determinants of MYC localization to target genes likely exist. Because little is known about the function of the central portion of the MYC protein, Thomas and colleagues screened for proteins that bind this region and identified WD repeat domain 5 (WDR5), a component of several chromatin modifying complexes, as a MYC binding partner that specifically interacts with the highly evolutionarily conserved MYC box IIIb (MbIIIb) motif within the MYC central region. Chromatin immunoprecipitation sequencing revealed a significant overlap between MYC and WDR5 binding sites, and mutation of the MbIIIb residues found to interact with WDR5 in a crystal structure prevented MYC binding to approximately 80% of its target sites across the genome, implicating WDR5 as a key cofactor of MYC that is broadly required for its binding to chromatin. Consistent with these findings suggesting that the interaction with WDR5 is required for the biologic activity of MYC, WDR5 binding–deficient MYC mutants were incapable of reprogramming mouse embryonic fibroblasts to induced pluripotent stem cells when expressed with OCT3/4, SOX2, and KLF4 and showed a dramatically reduced capacity to induce tumor growth in vivo compared with wild-type MYC. In addition to identifying WDR5 as a MYC binding partner and a role for the MbIIIb motif as a WDR5 interaction module, these findings suggest that targeting the interaction between MYC and WDR5 may be a tractable and effective strategy to directly block MYC transcriptional activity and suppress MYC-driven tumor growth.

Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell 2015 Mar 26 [Epub ahead of print].

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