SUMMARY A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here we find that DNA methylation of the TERT CpG Island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter-mutant cancers. Finally, in several cancers DNA methylation levels at the TERT CGI correlate with altered patient survival.
Isopropylmalate dehydrogenase (IPMDH) and 3-(2-methylthio)ethylmalate dehydrogenase catalyze the oxidative decarboxylation of different -hydroxyacids in the leucine-and methionine-derived glucosinolate biosynthesis pathways, respectively, in plants. Evolution The evolution of specialized metabolic pathways from primary metabolism provides plants with the ability to generate molecules that contribute to their survival (1). The classic cycle of gene duplication and divergence of sequence that leads to new substrate specificities is at the core of how plants diversify metabolism for new purposes. One example of this process is the evolution of enzymes from leucine biosynthesis into variants for the production of sulfur-containing glucosinolates in plants of the order Brassicales (2-4). In the biosynthesis of methionine-derived glucosinolates, the sequential addition of methylene groups that leads to elongated aliphatic glucosinolates mimics the reactions in leucine biosynthesis (2).In the leucine biosynthesis pathway of plants and microbes, the NAD ϩ -dependent enzyme isopropylmalate dehydrogenase (IPMDH) 3 catalyzes the oxidation and decarboxylation of 3-isopropyl-L-malate (IPM) to 4-methyl-2-oxovalerate ( Fig. 1) (2). Subsequent transamination of 4-methyl-2-oxovalerate produces leucine. In the synthesis of aliphatic glucosinolate biosynthesis, the corresponding 3-malate derivative (i.e. 3-(2Ј-methylthio)ethylmalate) is produced from methionine. Branched-chain aminotransferases catalyze the deamination of methionine to 4-methythio-2-oxobutanoic acid (5, 6). Subsequent steps performed by methylthioalkylmalate synthase and an isopropylmalate isomerase homolog generate 3-(2Ј-methylthio)ethylmalate) (7, 8), which undergoes oxidation and decarboxylation to yield 5-methylthiol-2-oxopentoate ( Fig. 1) (9, 10). This product can then be transaminated for further elongation of the aliphatic moiety to yield C4 to C8 aliphatic glucosinolates (2).In plants, complementation of yeast with a Leu2 mutation by genes from canola, potato, and Arabidopsis thaliana identified IPMDH in the leucine biosynthesis pathway (11-13). Later studies of the three IPMDH isoforms in Arabidopsis (AtIPMDH1-3) revealed differences in the biochemical properties and metabolic contributions of each protein (9, 10). Steady-state kinetic analysis of AtIPMDH1-3 showed that each enzyme catalyzed the conversion of 3-isopropylmalate to 4-methyl-2-oxovalerate; however, the catalytic efficiency of AtIPMDH1 was up to 40-fold lower than the two other isoforms (9, 10). Analysis of Arabidopsis T-DNA insertion mutants that disrupted AtIPMDH1 showed decreased levels of C4 -C8 aliphatic glucosinolates and leucine. The loss of glucosinolate synthesis could be complemented by expression of AtIPMDH1 but not by expression of either AtIPMDH2 or AtIPMDH3 (10). T-DNA mutants of AtIPMDH2 and AtIPMDH3 reduced leucine levels but did not significantly alter glucosinolate production in Arabidopsis (14). Moreover, the Arabidopsis AtIPMDH2/AtIPMDH3 double mutant had defects in...
In the originally published version of this article, in the legend to Figure S1 (which relates to main Figure 1C), the definition of TERT status in cell lines as ''wt, wild type promoter with biallelic expression'' should instead be ''wt, wild type promoter; some of these are BAE (N = 43; Huang et al., 2015) and some are undetermined.'' This correction does not change any of the stated conclusions of our paper but is reported here so that others using these cell lines will not be misled. The authors regret this error.
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