Control of nucleotide biosynthesis by the MYC oncoprotein: Old friends get reacquainted

Abstract

The MYC oncoprotein drives cell cycle progression in both normal cells and human tumors. In fact, MYC overexpression provides such a proliferative advantage that a remarkable percentage of human tumors exhibit elevated MYC levels. 1 Hyper-proliferation requires that cells ramp up biosynthetic pathways for protein and lipid production, energy metabolism and DNA replication. Evidence for MYC controlling multiple points in the pathways leading to protein synthesis and energy metabolism has come from a variety of sources in recent years. 2 The study by Mannava published in this issue, along with similar findings from the Dang group, now firmly links MYC to the production of nucleotides required as building blocks for DNA synthesis. After finding that human melanoma cell lines required MYC for optimal proliferation, Mannava et al. identified MYC target genes that might explain this requirement by using expression profiling. Among the targets they identified were genes encoding enzymes that regulate several rate-limiting steps in nucleotide biosynthesis. At least three of these enzymes, thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2), are encoded by direct MYC target genes. As predicted by this set of observations, MYC depletion resulted in decreased cellular dNTP levels. Using the gold standard for epistatis experiments, Mannava ultimately show that ectopic expression of TS, IMPDH2 and PRPS2 partially rescues the proliferative defect caused by MYC depletion in melanoma cells.These observations are strengthened by the independent findings of the Dang group. Dang et al. also identified IMPDH2 (and IMPDH1) as a MYC target using an unbiased screen for MYC binding sites in the genome. 3 These studies were conducted in different cell types than the melanomas used by Manneva et al. suggesting that the link between MYC and nucleotide biosynthesis holds true across very distinct lineages. More broadly, the Dang group, unlike Manneva et al. found that genes involved in nucleotide metabolism were statistically overrepresented among their list of MYC targets.These two exciting studies appear against the backdrop of previous work linking MYC to this pathway. A number of years ago, similar excitement was generated by evidence that MYC controlled transcription of CAD, 4 the gene encoding the first three enzymes required for pyrimidine biosynthesis. While CAD is clearly regulated by MYC in many settings, subsequent studies showed that its levels were not linked to MYC in Burkitt's lymphoma. 5 Thus, these new studies linking MYC to nucleotide biosynthesis renew optimism that we might now have the mechanistic explanation for how MYC provides one of the essential sets of building blocks necessary as it pushes cell proliferation.Relevant to these findings, a study from the Dalla-Favera group last year showed a role for MYC in the function of origins of DNA replication. 6 Coupled with a role for MYC in generating the nucleotides necessary for DNA synthesis, t...

Emerging roles of Myc in stem cell biology and novel tumor therapies

“…Knockdown of pyrimidine synthesis genes mainly regulated by c-Myc results in the suppression of the proliferation of the colorectal tumor cells, which is quite similar to c-Myc knockdown. In contrast, the knockdown of metabolic enzymes-coding genes necessary for purine synthesis does not affect the proliferation of colorectal cancer cells [ 162 – 164 ]. As many as 231 genes have been identified in a total of more than 300 metabolic reactions, including the pentose phosphate pathway, purine/pyrimidine synthesis pathway, fatty acid oxidation pathway and MAPK signaling pathway [ 162 ].…”

A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation

“…PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP, while PRPS2 is largely resistant to this feedback inhibition 20, 21 . Mutations of PRPS1, which reduced feedback inhibition of purine biosynthesis, were identified in relapsed childhood B cell acute lymphoblastic leukemia (ALL) 22 , whereas PRPS2 and enhanced PRPS2 expression were shown to be crucial for lymphoma and melanoma cell survival 23–25 . However, the mechanism through which the aberrant posttranslational regulation of PRPS contributes to tumor development is unknown.…”

Human Cytomegalovirus Can Procure Deoxyribonucleotides for Viral DNA Replication in the Absence of Retinoblastoma Protein Phosphorylation

“…The multiple modulators of the Rb-E2F pathway may make the absence of any single one insignificant. Also, in addition to the Rb/E2F pathway, nucleotide biosynthesis is also controlled by the c-myc protein (61). As HCMV activates c-myc expression at very early times postinfection (62), it is likely that c-myc also contributes to providing nucleotides in support of HCMV vDNA replication.…”