MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis (RNA-Seq)

MYC is a potent oncogene associated with aggressive disease in many distinct tumor types. Transforming members of the MYC family (MYC, MYCL1, MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology Boxes (MBs). Here, we conduct proteomic profiling of the MB interactomes, demonstrating that half of MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses revealed that two MBs are universally required for transformation. MBII interaction with acetyltransferase-containing complexes results in histone hyperacetylation and is essential for MYC-dependent tumor initiation. By contrast, MB0 interacts with transcription elongation factors through direct binding to the general transcription factor TFIIF, and deletion of MB0 severely inhibits tumor growth but is dispensable for tumor initiation. Notably, the full transforming activity of MYC can be restored upon co-expression of MB0 and MBII deletion mutants, indicating that these two regions confer unique biological functions, each required for oncogenic MYC activity. Overall design: RNA-seq analysis was conducted in TET21 cells (n=4, for each of the MYC deletion mutant ectopycally expressed) to determine the nature of the MB transcriptomes, and ChIPseq was conducted on WT-MYC TET21-expressing cells to determine MYC binding (n=1).

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Kalkat M, Resetca D, Lourenco C, Chan PK, Wei Y, Shiah YJ, Vitkin N, Tong Y, Sunnerhagen M, Done SJ, Boutros PC, Raught B, Penn LZ