Abstract
Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. The evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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Abbreviations
- ACD
- Adrenocortical Dysplasia Protein Homolog (unofficial name TPP1)
- ARF
- A-Raf Proto-Oncogene Serine/Threonine-Protein Kinase
- ARID2
- AT-Rich Interaction Domain 2
- ATAC
- Assay for Transposase-Accessible Chromatin
- BRAF
- B-Raf Proto-Oncogene, Serine/Threonine Kinase
- CDKN2A
- Cyclin-Dependent Kinase Inhibitor 2A
- CRAF
- C-Raf Proto-Oncogene, Serine/Threonine Kinase
- CST
- CTC1-STN1-TEN1 complex
- CTNNB1
- Catenin Beta 1
- ENCODE
- Encyclopedia of DNA Elements
- ELF
- E74 Like ETS Transcription Factor
- ERK
- Extracellular Signal-Regulated Kinase
- ETS
- E26 Transformation-specific
- ETS1
- ETS Proto-Oncogene 1, Transcription Factor
- ETS2
- ETS Proto-Oncogene 2, Transcription Factor
- ETV5
- ETS Variant Transcription Factor 5
- GABPA
- GA Binding Protein Transcription Factor Subunit Alpha
- GABPB1
- GA Binding Protein Transcription Factor Subunit Beta 1
- hESC
- Human Embryonic Stem Cells
- IDH
- Isocitrate Dehydrogenase
- MAPK
- Mitogen-Activated Protein Kinase
- NF-kB
- Nuclear Factor Kappa B Subunit
- NRAS
- Neuroblastoma RAS Viral Oncogene Homolog
- POT1
- Protection of Telomere
- RAP1
- Repressor/activator Protein 1
- RTEL
- Regulator of Telomere Elongation Helicase 1
- TERC
- Telomerase RNA Component
- TERT
- Telomerase Reverse Transcriptase
- TIN2
- TRF1 Interacting Nuclear Factor 2
- TRAIL-R2
- Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 2
- TRF1
- Telomeric Repeat Binding Factor 1
- TRF2
- Telomeric Repeat Binding Factor 2