Genome recognition by MYC

Abstract

MYC dimerizes with MAX to bind DNA, with a preference for the E-box consensus CACGTG and several variant motifs. In cells, MYC binds DNA preferentially within transcriptionally active promoter regions. Although several thousand promoters are bound under physiological (low MYC) conditions, these represent only a fraction of all accessible, active promoters. MYC overexpression-as commonly observed in cancer cells-leads to invasion of virtually all active promoters, as well as of distal enhancer elements. We summarize here what is currently known about the mechanisms that may guide this process. We propose that binding site recognition is determined by low-affinity protein-protein interactions between MYC/MAX dimers and components of the basal transcriptional machinery, other chromatin-associated protein complexes, and/or DNA-bound transcription factors. DNA binding occurs subsequently, without an obligate requirement for sequence recognition. Local DNA scanning then leads to preferential stabilization of the MYC/MAX dimer on high-affinity DNA elements. This model is consistent with the invasion of all active promoters that occurs at elevated MYC levels, but posits that important differences in affinity persist between physiological target sites and the newly invaded elements, which may not all be bound in a productive regulatory mode. The implications of this model for transcriptional control by MYC in normal and cancer cells are discussed in the light of the latest literature.

Figure 1.

Different modes of MYC/MAX interaction with DNA. Modes 1–3 not only represent different possible modalities of interaction with genomic sites, but are also postulated to constitute the succession of events by which MYC/MAX dimers are driven to their physiological binding sites (mode 3), as discussed in the text. No binding: access of MYC/MAX to potential sites may be restricted by chromatin or nuclear organization, or by the lack of positive cues for selective recruitment (see text). Indeed, it is important to consider that a large majority of E-box motifs in the genome shows no significant MYC/MAX binding. Mode 1: binding to open chromatin via protein–protein interactions, but without direct DNA contacts. Examples of potentially interacting proteins or protein complexes are schematically represented (HAT, histone acetyltransferase complex; Med, Mediator complex). Mode 2: as mode 1 with additional DNA binding, but in a nonsequence-specific, low-affinity manner. Mode 3: same as above, but stabilized by high-affinity DNA contacts.