MYC: a complex problem

Abstract

The MYC protooncogene functions as a universal amplifier of transcription through interaction with numerous factors and complexes that regulate almost every cellular process. However, a comprehensive model that explains MYC's actions and the interplay governing the complicated dynamics of components of the transcription and replication machinery is still lacking. Here, we review the potency of MYC as an oncogenic driver and how it regulates the broad spectrum of complexes (effectors and regulators). We propose a 'hand-over model' for differential partitioning and trafficking of unstructured MYC via a loose interaction network between various gene-regulatory complexes and factors. Additionally, the article discusses how unstructured-MYC energetically favors efficient modulation of the energy landscape of the transcription cycle.

Keywords: DNA topology; MYC; MYC–topoisome complex; RNA polymerase; intrinsically disordered proteins; multistep reactions; protein complexes; topoisomerase; transcription cycle.

Figure 1.. How does MYC deliver regulatory molecules to promoters?

As a universal amplifier, MYC has been presumed to deliver effectors to its target sites through binding with promoter-proximal E-boxes or by directly binding with the TSS-bound transcription machinery, as shown. First, (A) MYC might participate in a huge megacomplex encompassing its interaction partners or sub-complexes. This master complex associates with chromatin and engages with E-boxes, or promoters via TSS-bound transcription machinery. Second, (B) The universal delivery service of MYC might be implemented by associating stochastically with individual complexes, and then depending upon the spatial and target constraints, delivering these complexes to target sites in a reversible manner. Possibly, such association and recruitment would sustain higher effector concentrations at TSSs and enhancers than would be supported by diffusion in the absence of MYC. Third, (C) MYC’s ability to permeate into different phase-separated regions might help in materialize a loose or transient network between its various cargoes comprised of gene regulatory complexes and factors varying according to their spatial and temporal flux. In a hand-over model, unstructured MYC would encounter these loose interactors reversibly, and the success of each molecular encounter would depend upon the reaction frequency and the collision rate as intermediates are stochastically handed over from one step to another. According to this model, fast association- dissociation kinetics would foster the rapid transfer of MYC-bearing complexes, subcomplexes or regulatory effectors through the various stages of the transcription-cycle in a timely and coordinated manner resulting in universal amplification by MYC. Further, MYC would be removed from genes by E3-directed poly-ubiquitin directed pathways and that may be inextricably coupled with its ability to regulate transcription activation/amplification.

Figure 2.. MYC regulates the energy landscape of the transcription cycle.

The conformational dynamics of unstructured MYC empower efficient remodeling of energy landscape to drive the transcription cycle through a still incompletely enumerated set of transitions that regulate the magnitude and precision of promoter output in general or may be exploited at individual genes or gene sets. In a multistep, sequential reaction, the upregulation of the ensemble of the slowest, rate-determining steps increases reaction output. MYC sequentially ferries complexes into TSSs (for closed-complex formation, DNA melting, promoter escape, polymerase pausing and pause release) to modify the energy landscape (solid and dotted lines shows with and without MYC, respectively). Regulating a multi-step process is always complicated as the same parameters (MYC) that drive an individual reaction forward by lowering the energy barrier to the transition state (solid line as shown in the figure) or deepen the product energy well (solid line), expedite reaction reversal or hinder progression through the next step, respectively. The reduced transition-state energy facilitates back reaction, while a deeper product-well makes it tougher to push those intermediate products uphill to the next transition state. To keep the energy landscape tilted downhill to support steady, irreversible reaction progress, energy must be consumed to continuously modulate barriers in the reaction pathway as the products of one reaction become the substrates for the next. The discharge/removal of MYC by ubiquitylation, proteasome degradation or other modifications, imparts direction and control over the multistep process by indicated complexes throughout the transcription. (E_a indicates activation energy, High and low MYC are shown in Red and pink, respectively). (Adapted from [105])