Myc up-regulates formation of the mRNA methyl cap

Abstract

The Myc proteins c-Myc and N-Myc are essential for development and tissue homoeostasis. They are up-regulated by growth factors and transmit the signal for cell growth and proliferation. Myc proteins are also prominent oncogenes in many human tumour types. Myc proteins regulate the transcription of protein-encoding mRNAs and the tRNAs and rRNA which mediate mRNA translation into protein. Myc proteins also up-regulate translation by increasing addition of the 7-methylguanosine cap (methyl cap) to the 5' end of pre-mRNA. Addition of the methyl cap increases the rate at which transcripts are translated by directing RNA modifications and translation initiation. Myc induces methyl cap formation by promoting RNA polymerase II phosphorylation which recruits the capping enzymes to RNA, and by up-regulating the enzyme SAHH (S-adenosylhomocysteine hydrolase), which neutralizes the inhibitory by-product of methylation reactions. Myc-induced cap methylation is a major effect of Myc function, being necessary for activated protein synthesis, cell proliferation and cell transformation. Inhibition of cap methylation is synthetic lethal with elevated Myc protein expression, which indicates the potential for cap methylation to be a therapeutic target.

MYC‐associated and double‐hit lymphomas: A review of pathobiology, prognosis, and therapeutic approaches

“…Although the transcriptional role of MYC has been well described, there are also nontranscriptional functions that only recently have been appreciated, including regulation of mRNA translation and direct regulation of DNA replication (for a review, see Cole and Cowling). For instance, MYC directly promotes methyl cap formation on the 5′ end of pre‐mRNA for many genes, including cyclin D1 and CDK‐9, and resulting in enhanced mRNA translation . Recent preclinical models have further demonstrated that MYC binds directly to, and promotes the activity of, replication complexes responsible for DNA synthesis, such that MYC levels correspond with the degree of DNA replication …”

“…For instance, MYC directly promotes methyl cap formation on the 5 0 end of pre-mRNA for many genes, including cyclin D1 and CDK-9, and resulting in enhanced mRNA translation. 19 Recent preclinical models have further demonstrated that MYC binds directly to, and promotes the activity of, replication complexes responsible for DNA synthesis, such that MYC levels correspond with the degree of DNA replication. 20…”

mRNA quality control at the 5’ end

“…And/or, as emerging evidence suggests, this is the result of active regulation to mRNA capping. For instance, it has been reported that importin-α stimulates general cap methylation (Wen and Shatkin, 2000), Myc regulates the cap methylation of many mRNAs (Cowling and Cole, 2007;2010;Cowling, 2010), and nutrient starvation caused a general decrease in cap methylation (Jiao et al, 2010). The regulatory factors of mRNA capping, together with the capping quality control mechanism, might provide yet another layer of regulation to gene expression.…”

Functional analysis of anS-adenosylhomocysteine hydrolase homolog of chestnut blight fungus

“…The mRNA level of SAHH is found to be significantly decreased in human tumors (Leal et al, 2008). The oncogenic transcription factor Myc induces methyl-cap formation by promoting phosphorylation of RNA polymerase II and increasing the SAHH activity (Cowling, 2010). Recent studies reveal that inhibitors of SAHH catalysis have multiple pharmacologic functions, including anticancer, antivirus, and antiparasite (Bray et al, 2000;Nakanishi, 2007;Cai et al, 2009;Sun et al, 2009).…”