Crossroads of telomere biology and anticancer drug discovery.
Hiroyuki SeimiyaPublished in: Cancer science (2020)
The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.
Keyphrases
- copy number
- papillary thyroid
- dna methylation
- genome wide
- transcription factor
- squamous cell
- gene expression
- mitochondrial dna
- drug discovery
- poor prognosis
- endothelial cells
- public health
- lymph node metastasis
- cell proliferation
- small molecule
- induced apoptosis
- palliative care
- cell cycle arrest
- long non coding rna
- young adults
- childhood cancer
- binding protein
- endoplasmic reticulum stress
- dna repair