EDITOR'S CHOICE IN GENETICS & GENOMICS
J.L. Stern et al., “Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers,” Genes Dev, doi:10.1101/gad.269498, 2015.
Chromosome ends are slightly shortened with each DNA replication. Terminal repetitive sequences called telomeres buffer coding DNA from this fate. In stem cells, telomerase extends the telomeres so that cell division can continue, perhaps indefinitely. In somatic cells, telomerase is inactive in part because the gene encoding telomerase’s catalytic subunit, telomerase reverse transcriptase (TERT), is epigenetically silenced. In most cancers, however, telomerase is again turned on and aids proliferation.
In 2013, researchers found two mutations in the TERT promoter that occur frequently in cancer cell lines and are tied with TERT expression.
To probe the mechanism of TERT activation, Josh Stern, a postdoctoral fellow in the lab of Thomas Cech at the University of Colorado Boulder, studied cancer cell lines that were heterozygous for one of these TERT mutations. Stern and his colleagues determined that the mutant TERT allele had histone methylation marks associated with gene activation and was transcribed, whereas the wild-type allele bore other histone methylation marks characteristic of gene silencing and was not transcribed.
“It’s very nice biochemical work to show that a single-base-pair mutation in the cancer genome activates the expression of the telomerase gene,” says Dana-Farber Cancer Institute’s Franklin Huang.
“Telomerase is a fantastic therapeutic target for cancers because so many cancers are absolutely reliant on telomerase,” says Stern. “These TERT promoter mutations only occur in cancer, so if we can understand the mechanism, then we can potentially develop a highly specific cancer therapeutic.”