Transcription-independent functions of MYC: regulation of translation and DNA replication

Abstract

MYC is a potent oncogene that drives unrestrained cell growth and proliferation. Shortly after its discovery as an oncogene, the MYC protein was recognized as a sequence-specific transcription factor. Since that time, MYC oncogene research has focused on the mechanism of MYC-induced transcription and on the identification of MYC transcriptional target genes. Recently, MYC was shown to control protein expression through mRNA translation and to directly regulate DNA replication, thus initiating exciting new areas of oncogene research.

Figure 1. The conserved regions of MYC

The three MYC proteins (MYC, MYCN and MYCL) are encoded by separate genes with distinct developmental regulation, but all three have been directly implicated in cancer. The N terminus of MYC contains the transactivation domain and the C terminus contains the DNA-binding domain. The MYC boxes I, II, III and IV are indicated in red. The basic helix-loop- helix/Leu zipper (bHLH/LZ) domain is indicated in green. MYC box II (MBII) has been shown to have a crucial role in most of the biological activities of MYC. Note that MBIV is not a component of the minimal DNA-binding domain but does influence DNA binding in vivo.

Figure 2. Mechanisms of MYC-induced transcription

a | MYC recruits histone acetyltransferases, which promote localized modification of chromatin through acetylation of nucleosomes. MYC-associated factor-X (MAX) dimerizes with MYC to create a functional DNA-binding complex that preferentially recognizes the consensus sequence CACGTG. The MYC transactivation domain recruits acetyltransferase complexes that contain transformation/transcription-domain-associated protein (TRRAP) and either general control of amino-acid-synthesis protein-5 (GCN5) or TIP60, which preferentially acetylate histones H3 or H4, respectively. MYC can also recruit p300/CReB-binding protein (CBP). These complexes alter the acetylation of nucleosomes around MYC target genes, and these acetylation marks might also recruit other nuclear factors that influence transcription, such as the SWI/SNF chromatin-remodelling complex (not shown). b | MYC recruits basal transcription factors and promotes the clearance of promoters through RNA polymerase (pol) II. RNA pol II is frequently paused on promoters after phosphorylation of Ser5 on the RNA pol II C-terminal domain (CTD) and synthesis of a short (20–40 base) segment of mRNA. The MYC protein can promote a paused RNA pol to continue transcription of the mRNA by recruiting the P-TeFb (positive transcription-elongation factor-b) complex, which phosphorylates the CTD on Ser2 and promotes transcriptional elongation.

Figure 3. Mechanism of MYC-induced mrNa cap methylation

MYC promotes recruitment of the transcription factor TFIIH kinase to promoters and RNA polymerase (pol) II phosphorylation. Increased RNA pol II phosphorylation increases cap RNA methyltransferase (RNMT) recruitment and/or activity, which correlates with MYC-dependent mRNA cap methylation. At direct MYC target genes (left), TFIIH enhances the recruitment or activity of the cap RNMT to increase the fraction of cap methylated mRNA. Direct binding of MYC also stimulates a modest increase in transcription through TFIIH or acetyltransferases (see FIG. 2). At other promoters (right), MYC stimulates mRNA cap methylation through TFIIH stimulation by the MYC transactivation domain and through the subsequent recruitment or activation of RNMT by C-terminal domain phosphorylation. In doing so, MYC functions as a transcription-independent factor. Activation of direct targets is MYC-associated factor-X (MAX)-dependent (left), whereas activation of transcription-independent targets is MAX-independent (right).