Exciting new studies of TERT regulation in cancer have identified activating mutations in the TERT promoter (which drives gene expression). These promoter mutations (TPM) are critical for the reactivation of telomerase expression and typically only occur on a single copy of the gene in the cells, and so are heterozygous. Thus, these mutant cells also harbor transcriptionally silent TERT alleles.
These mutations are cancer-specific i.e. they do not occur in stem cells. Thus, the significance of these discoveries is that for the first time we know that many cancers regulate their immortal phenotype in distinct ways from normal stem cells. This creates the opportunity to selectively target replicative immortality in cancers without affecting normal cells.
TPM are the third most common of all recurrent mutations in cancer, and the most common recurrent non-coding mutation in cancer so far discovered.
These mutations recruit a specific transcription factor to the mutated sequence to drive TERT expression and are accompanied by numerous changes to the promoter that differ markedly from both normal stem cells as well as tumors that lack TPM.
This model system also revealed that the inactive allele recruits polycomb repressive complex 2 (PRC2) which may cooperate with DNA methylation (5mC) at this locus to maintain repression.
Key questions about the origin and biology of these tumors include:
Why do only some cancers drive their immortal phenotype through TERT promoter mutations?
Within a cancer type, why do only certain tumors arise with these TERT promoter mutations?
1. Stern J.L., Paucek R.D., Huang F.W., Ghandi M., Nwumeh R., Costello J., Cech T.R. Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant TERT genes. Cell Reports (2017). https://doi.org/10.1016/j.celrep.2017.12.001
2. Stern J.L., Theodorescu D., Vogelstein B., Papadopoulos N., Cech T.R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 29, 2219-24 (2015). http://www.genesdev.org/cgi/doi/10.1101/gad.269498.115
Copyright © 2018 telomerase regulation - All Rights Reserved (at the least the parts that aren't already copyrighted by someone else).