Telomere and Telomerase Therapeutics in Cancer

Xu, Yang; Goldkorn, Amir

doi:10.3390/genes7060022

Cited by 90 publications

(104 citation statements)

References 168 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…TERT upregulation or reactivation seems to be associated with several “hallmarks of cancer” including increased mitochondrial activity, DDR signaling, and WNT/β-catenin signaling [42,43,44]. More recently, it was shown that TERT regulates MYC-driven oncogenesis independently of its reverse transcriptase activity [13]. TERT-null mice showed a delayed development of MYC-induced lymphomagenesis, while Terc-null mice did not [45].…”

Section: Current Therapies Related To Telomeres and Telomerasementioning

confidence: 99%

“…When TRF1, TRF2, or POT1 are not functioning properly or dissociate from the telomere, the t-loop unfolds, exposing the telomere, which induces DDRs such as apoptosis and senescence [1,11,12]. It is thought that the T-loop is also stabilized by the guanine-rich (G-rich) character present in telomeres [6,12,13], allowing the telomere 3’ overhang to take on a G-quadruplex structure, a secondary structure formed from the hydrogen bonding of guanine residues in tetrad formations (Figure 1). These G-quadruplexes stack together at the D-loop, the area where the 3’ end of the telomere penetrates the duplex region [2,10].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

View full text Add to dashboard Cite

Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effe...

show abstract

Section: Current Therapies Related To Telomeres and Telomerasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Inhibitors of telomerase activity have entered clinical development for treating various types of human cancers, including multiple myeloma and breast, non-small cell lung, and pancreatic cancers, with several advancing to phase III trials (Xu and Goldkorn, 2016). The primary short-coming of telomerase inhibitors, however, is that even after destroying telomerase activity, the cancer cells must go through multiple rounds of DNA replication before telomere attrition results in replicative senescence.…”

Section: Introductionmentioning

confidence: 99%

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Zeng

Hernandez-Sanchez

et al. 2018

Cell Reports

View full text Add to dashboard Cite

SUMMARY Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy.

show abstract

“…78 Additionally, mutations in the protein or RNA components of telomerase are associated with the bone marrow failure syndrome dyskeratosis congenita, a marked decrease in telomerase activity, and shortened telomeres. 79 Thus, an improved structural understanding of the mechanics of telomerase holds significant therapeutic implications.…”

Section: Telomerase: a Multifunctional Rna Plays Essential Roles In Tmentioning

confidence: 99%

Structural Roles of Noncoding RNAs in the Heart of Enzymatic Complexes

Martin

Reiter

2016

Biochemistry

View full text Add to dashboard Cite

Over billions of years of evolution, nature has embraced proteins as the major workhorse molecules of the cell. However, nearly every aspect of metabolism is dependent upon how structured RNAs interact with proteins, ligands, and other nucleic acids. Key processes, including telomere maintenance, RNA processing, and protein synthesis, require large RNAs that assemble into elaborate three-dimensional shapes. These RNAs can (i) act as flexible scaffolds for protein subunits, (ii) participate directly in substrate recognition, and (iii) serve as catalytic components. Here, we juxtapose the near atomic level interactions of three ribonucleoprotein complexes: ribonuclease P (involved in 5′ pre-tRNA processing), the spliceosome (responsible for pre-mRNA splicing), and telomerase (an RNA-directed DNA polymerase that extends the ends of chromosomes). The focus of this perspective is profiling the structural and dynamic roles of RNAs at the core of these enzymes, highlighting how large RNAs contribute to molecular recognition and catalysis.

show abstract

Telomere and Telomerase Therapeutics in Cancer

Cited by 90 publications

References 168 publications

Treating Cancer by Targeting Telomeres and Telomerase

Treating Cancer by Targeting Telomeres and Telomerase

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Structural Roles of Noncoding RNAs in the Heart of Enzymatic Complexes

Contact Info

Product

Resources

About