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.

c-MYC partners with BPTF in human cancer

“…Recently Sab R et al proposed a sequential model for c-MYC binding site recognition whereby low-affinity protein-protein interactions between c-MYC:MAX and chromatin-associated complexes and/or transcription factors precede c-MYC binding to DNA. 7 Consistent with these findings, Thomas et al reported that the interaction between c-MYC and the chromatin remodeler WD repeat domain 5 (WDR5, present in multiple chromatin regulatory complexes such as H3K4 methyltransferases) is required for c-MYC recruitment to DNA and biological activity. 9 Once bound to its targets, c-MYC recruits co-factors that further modify the chromatin, resulting in increased DNA accessibility and transcriptional activation.…”

Error-prone Translesion Synthesis Past DNA-Peptide Cross-links Conjugated to the Major Groove of DNA via C5 of Thymidine

“…This peptide is derived from the c-Myc protein, a transcription factor that plays a key role in cell cycle progression, apoptosis, and cellular transformation. c-Myc regulates the expression of Ͼ15% of all human genes and is up-regulated in many types of cancer (64,65). Because of its strong affinity for DNA and the presence of nucleophilic amino acids in its structure, c-Myc is likely to participate in DNA-protein cross-linking upon exposure to bis-electrophiles and reactive oxygen species.…”

Common Mechanisms of Onset of Cancer and Neurodegenerative Diseases

“…1) In addition to the bHLHzip region, Myc-boxes I and II are also essential for transcription activity of c-Myc through association with the co-activator complex. [2][3][4] c-Myc is known to regulate transcription of more than 50% of genes present in cells, including genes related to metabolism, ribosomal synthesis and progression of the cell cycle, thereby leading to increase of cell mass. [3][4][5] We have found for the first time that c-Myc is a factor that regulates initiation of DNA replication 6) and that c-Myc binds to one of the replication origins located at the region upstream of the c-myc gene, which also acts as a transcriptional enhancer, in association with origin recognition complex (ORC) and sequence-specific DNA-binding protein Myc Single-Strand binding Proteins (MSSP), one of the c-Myc-binding proteins we identified.…”

“…[2][3][4] c-Myc is known to regulate transcription of more than 50% of genes present in cells, including genes related to metabolism, ribosomal synthesis and progression of the cell cycle, thereby leading to increase of cell mass. [3][4][5] We have found for the first time that c-Myc is a factor that regulates initiation of DNA replication 6) and that c-Myc binds to one of the replication origins located at the region upstream of the c-myc gene, which also acts as a transcriptional enhancer, in association with origin recognition complex (ORC) and sequence-specific DNA-binding protein Myc Single-Strand binding Proteins (MSSP), one of the c-Myc-binding proteins we identified. [7][8][9][10][11] This case is also true for the replication origin/enhancer in the heat shock protein 70 gene to which c-Myc/NF-Y binds, 12) giving rise to the idea of a concerted mechanism of DNA replication and transcription.…”