Myc and mRNA capping

Abstract

c-Myc is upregulated in response to growth factors and transmits the signal to proliferate by altering the gene expression landscape. When genetic alterations result in growth factor-independent c-Myc expression, it can become an oncogene. The majority of human tumour types exhibit a degree of c-Myc deregulation, resulting in unrestrained cell proliferation. c-Myc binds proximal to the promoter region of genes and recruits co-factors including histone acetyltransferases and RNA pol II kinases, which promote transcription. c-Myc also promotes formation of the cap structure at the 5' end of mRNA. The cap is 7-methylguanosine linked to the first transcribed nucleotide of RNA pol II transcripts via a 5' to 5' triphosphate bridge. The cap is added to the first transcribed nucleotide by the capping enzymes, RNGTT and RNMT-RAM. During the early stages of transcription, the capping enzymes are recruited to RNA pol II phosphorylated on Serine-5 of the C-terminal domain. The mRNA cap protects transcripts from degradation during transcription and recruits factors which promote RNA processing including, splicing, export and translation initiation. The proportion of transcripts with a cap structure is increased by elevating c-Myc expression, resulting in increased rates of translation. c-Myc promotes capping by promoting RNA pol II phosphorylation and by upregulating the enzyme SAHH which neutralises the inhibitory bi-product of methylation reactions, SAH. c-Myc-induced capping is required for c-Myc-dependent gene expression and cell proliferation. Targeting capping may represent a new therapeutic opportunity to inhibit c-Myc function in tumours. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.

Keywords: 7-methylguanosine; Capping; Transcription; c-Myc; mRNA.

Fig. 1

Diagram of the mRNA cap. The mRNA cap is 7-methylguanosine linked via a 5′ to 5′ triphosphate bridge to the first transcribed nucleotide. The first and second transcribed nucleotides can also be methylated on the ribose 2-hydroxyl position creating Cap1 and Cap2, respectively.

Fig. 2

mRNA cap synthesis. Nascent RNA is transcribed with a 5′ triphosphate, denoted ppp(5′)Np, where N is the first transcribed nucleotide. RNGTT has triphosphatase and guanylyltransferase activities and catalyses addition of the inverted guanosine cap to create, G(5′)ppp(5′)Np. RNMT is the cap methyltransferase which methylates the guanosine cap on the N-7 position to create Cap 0 m7G(5′)ppp(5′)Np.

Fig. 3

c-Myc regulated mRNA cap synthesis. c-Myc-Max binds proximal to transcription initiation sites, promotes TFIIH recruitment and RNA pol II phosphorylation. RNGTT and RNMT–RAM are recruited to the phosphorylated C-terminal domain of RNA pol II, where they catalyse mRNA cap (m7G) synthesis. The methylation reaction uses the methyl donor, SAM (s-adenosyl methionine), and produces the inhibitory bi-product SAH (s-adenosyl homocysteine). c-Myc upregulates SAHH (S-adenosyl homocysteine hydrolase) which catalyses hydrolysis of SAH producing adenosine and homocysteine (HCY).