TERT promoter mutations in telomere biology.
Telomere repeats at chromosomal ends, critical to genome integrity, are maintained through an elaborate network of proteins and pathways. Shelterin complex proteins shield telomeres from induction of DNA damage response to overcome end protection problem. A specialized ribonucleic protein, telomerase, maintains telomere homeostasis through repeat addition to counter intrinsic shortcomings of DNA replication that leads to gradual sequence shortening in successive mitoses. The biogenesis and recruitment of telomerase composed of telomerase reverse transcriptase (TERT) subunit and an RNA component, takes place through the intricate machinery that involves an elaborate number of molecules. The synthesis of telomeres remains a controlled and limited process. Inherited mutations in the molecules involved in the process directly or indirectly cause telomeropathies. Telomerase, while present in stem cells, is deactivated due to epigenetic silencing of the rate-limiting TERT upon differentiation in most of somatic cells with a few exceptions. However, in most of the cancer cells telomerase reactivation remains a ubiquitous process and constitutes one of the major hallmarks. Discovery of mutations within the core promoter of the TERT gene that create de novo binding sites for E-twenty-six (ETS) transcription factors provided a mechanism for cancer-specific telomerase reactivation. The TERT promoter mutations occur mainly in tumors from tissues with low rates of self-renewal. In melanoma, glioma, hepatocellular carcinoma, urothelial carcinoma and others, the promoter mutations have been shown to define subsets of patients with adverse disease outcomes, associate with increased transcription of TERT, telomerase reactivation and affect telomere length; in stem cells the mutations inhibit TERT silencing following differentiation into adult cells. The TERT promoter mutations cause an epigenetic switch on the mutant allele along with recruitment of pol II following the binding of GABPA/B1 complex that leads to mono-allelic expression. Thus, the TERT promoter mutations hold potential as biomarkers as well as future therapeutic targets.
Division of Molecular Genetic Epidemiology. Electronic address: b.heidenreich@dkfz.de.
Barbara
B
Heidenreich
Division of Molecular Genetic Epidemiology; German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: r.kumar@dkfz.de.
Rajiv
R
Kumar
D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D016615:Telomere
C509186:TERT protein, human; D019098:Telomerase
Mutations; Promoter; TERT; Telomerase; Telomeres