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Target gene-independent functions of MYC oncoproteins

Nature Reviews Molecular Cell Biology volume 21, pages 255–267 (2020)Cite this article

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Abstract

Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying their function has focused on the biology of their target genes. Detailed studies of MYC-dependent changes in RNA levels have provided contrasting models of the oncogenic activity of MYC proteins through either enhancing or repressing the expression of specific target genes, or as global amplifiers of transcription. In this Review, we first summarize the biochemistry of MYC proteins and what is known (or is unclear) about the MYC target genes. We then discuss recent progress in defining the interactomes of MYC and MYCN and how this information affects central concepts of MYC biology, focusing on mechanisms by which MYC proteins modulate transcription. MYC proteins promote transcription termination upon stalling of RNA polymerase II, and we propose that this mechanism enhances the stress resilience of basal transcription. Furthermore, MYC proteins coordinate transcription elongation with DNA replication and cell cycle progression. Finally, we argue that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes.

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Fig. 1: Protein domains of MYC and their canonical function.
Fig. 2: Models of gene regulation by MYC.
Fig. 3: MYC-associated proteins.
Fig. 4: A hand-over model of promoter-proximal function of MYC proteins.
Fig. 5: MYC binding at core promoters.

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Acknowledgements

We thank several colleagues in the field for numerous fruitful discussions and apologize to the many colleagues whose work we did not quote due to lack of space. The work in the authors’ laboratories is funded by grants from the European Research Council (AuroMYC, TarMyc) and the German Research Council (DFG).

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Authors and Affiliations

  1. Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany

    Apoorva Baluapuri, Elmar Wolf & Martin Eilers

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  1. Apoorva Baluapuri
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  2. Elmar Wolf
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  3. Martin Eilers
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Martin Eilers.

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The authors declare no competing interests.

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Nature Reviews Molecular Cell biology thanks William Tansey and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Phospho-degron

A short amino acid motif that is recognized by a ubiquitin ligase and promotes the degradation of the protein. Ubiquitin ligases often recognize degrons upon phosphorylation of a critical residue, hence the term phospho-degron.

Bio-ID techniques

Allow the systematic identification in living cells of proteins that are in close proximity to a protein of interest fused to a biotin ligase.

Promoter-proximal pausing

A transcription regulatory step, whereby RNA polymerase II pauses about 80 nucleotides downstream of the transcription start site.

R-loop

A three-stranded nucleic acid structure consisting of an RNA–DNA hybrid and the corresponding single strand of DNA.

Replication–transcription conflicts

Collusions of the transcription and replication machineries during S phase, which could result in DNA damage and genome instability.

Pattern recognition receptors

Cellular innate immunity factors that recognize molecules that are typical of pathogens.

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Baluapuri, A., Wolf, E. & Eilers, M. Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol 21, 255–267 (2020). https://doi.org/10.1038/s41580-020-0215-2

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