S-Adenosyl Homocysteine Hydrolase Is Required for Myc-Induced mRNA Cap Methylation, Protein Synthesis, and Cell Proliferation

Abstract

The c-Myc proto-oncogene promotes mRNA cap methylation, which is essential for almost all mRNA translation. The mRNA cap methylation reaction produces an inhibitory byproduct, S-adenosyl homocysteine. Here we report that Myc promotes upregulation of S-adenosyl homocysteine hydrolase (SAHH), an enzyme which hydrolyzes S-adenosyl homocysteine, thus neutralizing its inhibitory effects, and this is required for c-Myc-induced mRNA cap methylation. c-Myc-induced mRNA cap methylation was repressed by inhibiting the expression or activity of SAHH, whereas the same treatments did not have a significant effect on c-Myc-induced transcription or other c-Myc-dependent methylation events. The selective inhibition of mRNA cap methylation afforded by SAHH repression revealed that c-Myc-induced cap methylation could be correlated with the core c-Myc functions of protein synthesis, cell proliferation, and cell transformation.The Myc proteins c-Myc, N-Myc and L-Myc promote cell growth and proliferation and are essential for development (12,25). Deregulated expression of the Myc proteins results in unrestrained cell proliferation and promotes tumor formation. The c-Myc gene, in particular, is recognized to be a potent oncogene in many organs and tissues and is deregulated in a significant proportion of human tumors.The Myc proteins are basic helix-loop-helix leucine zipper (bHLH-LZ) proteins which form heterodimers with another such protein, Max. Myc-Max heterodimers form transcription factors which both activate and repress transcription (8,10,18,27). The Myc proteins have a major impact on cellular transcription, activating or repressing approximately 10% of RNA polymerase II (RNA pol II)-transcribed genes (mRNA and microRNA) and activating RNA pol I-and III-transcribed genes. Many cofactors which mediate Myc-regulated transcription have been isolated, with the majority of these regulating chromatin structure and the recruitment and activity of the RNA polymerases (8,12,38).Myc proteins have recently been found to regulate gene expression by promoting mRNA cap methylation (5, 9). The mRNA cap is an inverted 7-methylguanosine group added to the 5Ј end of RNA pol II-transcribed genes, which stabilizes the RNA and promotes splicing, nuclear export, and translation (1,14,35,36). The 7-methylguanosine cap is added to nascent RNA by the action of three enzymes. A triphosphatase removes the terminal phosphate of the first transcribed nucleotide, a guanylyltransferase adds GMP to create the guanosine cap, and an RNA guanine-7 methyltransferase methylates the guanosine cap at the N-7 position to create the 7-methylguanosine cap (36). Methylation of the guanosine cap is critical for mRNA binding to eukaryotic translation initiation factor 4E (eIF4E), the subsequent formation of the eIF4F complex, and the initiation of translation (14).mRNA cap methylation occurs predominantly during the early stages of transcription as the 5Ј end of the nascent RNA emerges from the RNA pol II complex (26,28). At this stage, the enzyme which catalyzes the a...

Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers

“…51 Adenosylhomocysteinase ( at 20q11) is required for Myc-induced mRNA cap methylation, protein synthesis and cell proliferation. 52,53 In 20q13.12, the transcription factor HNF4A manipulating polarity of epithelial cell showed facilitation in mouse intestine neoplasia. 54 WISP2 (WNT1 inducible signaling pathway protein 2/CCN5) influences the signaling pathway of transforming growth factor-α and the epithelial-mesenchymal transition.…”

Regulation of mRNA capping in the cell cycle

“…Transcription factors upregulate RNA pol II phosphorylation and methionine metabolism resulting in gene-specific regulation of mRNA cap methylation. [25][26][27][28] Furthermore, embryonic stem cell differentiation requires ERK1/2-dependent phosphorylation of RAM, which triggers its degradation and loss of pluripotency associated gene expression. 29 It seems likely that many other signaling pathways will be regulating mRNA capping enzymes.…”

Myc up-regulates formation of the mRNA methyl cap

“…Elevation of SAHH expression removes excess SAH and permits Mycinduced cap methylation. Myc also regulates methylation of other RNAs, DNA and proteins; however, when these methylations were investigated, they were not found to be dependent on up-regulation of SAHH [18]. Either the cap methyltransferase may experience higher local concentrations of SAH than the other methyltransferases, or the cap methyltransferase enzyme may be more sensitive to SAH levels.…”

“…Myc induces global changes in chromatin structure and this may also favour increased recruitment of the methyl cap-forming enzymes [17]. As described below, although recruitment of TFIIH is required, it is not sufficient for Mycregulated methyl cap formation [18].…”

“…SAH can be hydrolysed and thus neutralized in cells by the enzyme SAHH (S-adenosyl homocysteine hydrolase). Elevating Myc levels produces inhibitory concentrations of SAH, which must be removed in order for Myc-induced cap methylation to proceed (Figure 2) [18]. Myc increases expression of SAHH enzyme both by regulating its transcription and cap methylation.…”