Abstract
A protein interaction screen reveals 336 MYC-binding proteins that bind to distinct MYC homology boxes (MB).
Major finding: A protein interaction screen reveals 336 MYC-binding proteins that bind to distinct MYC homology boxes (MB).
Mechanism: Two MBs cooperate to promote tumorigenesis, MB0 by binding to TFIIF and MBII by binding to TRRAP-HAT.
Impact: Only a subset of MYC interactors promote tumorigenesis, an insight that may aid therapeutic targeting of MYC.
The MYC family proteins MYC, MYCL1, and MYCN are frequently deregulated in cancer. These proteins harbor six highly conserved regions termed MYC homology boxes (MB), but the mechanisms by which MYC promotes tumorigenesis and the contribution of the individual MBs are not well understood. To delineate the function of the MBs, Kalkat and colleagues conducted proteomic profiling to identify the binding partners of wild-type MYC and six deletion mutants each with one of the MBs deleted. A total of 336 MYC-interacting proteins were identified, and each MB deletion resulted in loss of a subset of interactors. Deletion of MB0 resulted in loss of 94 interacting partners, and deletion of MBII resulted in loss of 43 interacting partners including a previously identified histone acetyltransferase (HAT) complex component TRRAP. Only two of the MB domains, MB0 and MBII, were required for tumorigenesis. Deletion of MB0 or MBII suppressed cell proliferation in vitro and suppressed the growth of MYC-dependent breast cancer xenografts in vivo. MB0 and MBII had distinct functions in promoting transcription and tumorigenesis. RNA sequencing showed minimal overlap between the genes upregulated by each MB, indicating that each regulates a distinct set of genes. MBII interacted with TRRAP–HAT complexes to promote tumor initiation, and deletion of MBII suppressed MYC-mediated histone acetylation. In contrast, MB0 interacted directly with the TFIIF transcription elongation complex to regulate transcription and accelerate tumor growth. Coexpressing both the mutant lacking MB0 and the mutant lacking MBII was sufficient to rescue tumor growth, further indicating that MB0 and MBII have independent but complementary effects in tumor promotion. Collectively, these findings reveal two MYC domains that cooperate to drive tumorigenesis, insights that may have implications for the development of MYC-targeted therapies.
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