High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells

Pech, Matthew F.; Garbuzov, Alina; Hasegawa, Kazuteru; Sukhwani, Meena; Zhang, Ruixuan J.; Benayoun, Bérénice A.; Brockman, Stephanie A.; Lin, Shengda; Brunet, Anne; Orwig, Kyle E.; Artandi, Steven E.

doi:10.1101/gad.271783.115

Cited by 55 publications

(63 citation statements)

References 63 publications

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“…Telomerase function is a hallmark for self-renewal potential in cancer, iPS, and male germ cells [45]. Dysregulated DNA damage repair contributes to oncogenic adaptation accumulation, and change in metabolic maintenance of the cell aid in rapid growth (Warburg effect).…”

Section: Testicular Cancer Is a Disease Of Male Germ Cell Developmentmentioning

confidence: 99%

Genetic changes associated with testicular cancer susceptibility

Pyle

Nathanson

2016

Seminars in Oncology

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Testicular germ cell tumor (TGCT) is a highly heritable cancer primarily affecting young white men. Genome-wide association studies (GWAS) have been particularly effective in identifying multiple common variants with strong contribution to TGCT risk. These loci identified through association studies have implicated multiple genes as associated with TGCT predisposition, many of which are unique among cancer types, and regulate processes such as pluripotency, sex specification and microtubule assembly. Together the identification of these biological plausible genes converges upon pathways involved in male germ cell development and maturation, and suggests that perturbation of them confers susceptibility to TGCT, as a developmental defect of germ cell differentiation.

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Section: Testicular Cancer Is a Disease Of Male Germ Cell Developmentmentioning

confidence: 99%

Genetic changes associated with testicular cancer susceptibility

Pyle

Nathanson

2016

Seminars in Oncology

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“…3,6,[8][9][10][11] Telomerase is inactive in normal cells but in 85% of all primary tumors, germ line cells, stem cells, hematopoietic cells and other rapidly dividing cells, high telomerase activity is observed. 8,[12][13][14][15][16][17] Therefore, telomerase inhibition is considered as an attractive selective therapy for cancer. [18][19][20] The 5' to 3' strand of human telomeric DNA (Htel) consists of tandemly repeated d(TTAGGG) sequence which extends beyond the duplex DNA producing a 3' single-stranded overhang of 100-280 nucleotides in length.…”

Section: Introductionmentioning

confidence: 99%

Structural Dynamics of Lateral and Diagonal Loops of Human Telomeric G-Quadruplexes in Extended MD Simulations

Islam

Stadlbauer

Krepl

et al. 2018

J. Chem. Theory Comput.

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The NMR solution structures of human telomeric (Htel) G-quadruplexes (GQs) are characterized by the presence of two lateral loops complemented by either diagonal or propeller loops. Bases of a given loop can establish interactions within the loop as well as with other loops and the flanking bases. This can lead to a formation of base alignments above and below the GQ stems. These base alignments are known to affect the loop structures and relative stabilities of different Htel GQ folds. We have carried out a total of 217 μs of classical (unbiased) molecular dynamics (MD) simulations starting from the available solution structures of Htel GQs to characterize structural dynamics of the lateral and diagonal loops, using several recent AMBER DNA force-field variants. As the loops are involved in diverse stacking and H-bonding interactions, their dynamics is slow, and extended sampling is required to capture different conformations. Nevertheless, although the simulations are far from being quantitatively converged, the data suggest that multiple 10 μs-scale simulations can provide a quite good assessment of the loop conformational space as described by the force field. The simulations indicate that the lateral loops may sample multiple coexisting conformations, which should be considered when comparing simulations with the NMR models as the latter include ensemble averaging. The adenine-thymine Watson-Crick arrangement was the most stable base pairing in the simulations. Adenine-adenine and thymine-thymine base pairs were also sampled but were less stable. The data suggest that the description of lateral and diagonal GQ loops in contemporary MD simulations is considerably more realistic than the description of propeller loops, though definitely not flawless.

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“…While germ line cells, stem cells, and select others including cardiovascular cells do express detectable levels of telomerase, it is mostly quiescent, and most normal cells have minimal or no detectable telomerase activity [14,15,16,17]. Telomerase confers cellular immortality through the addition of TTAGGG tandem repeats to the 3’ end of the telomere, thereby maintaining stable telomere length, preventing the induction of DDRs by the critical shortening of telomeres, and allowing continued proliferation of neoplastic cells [7].…”

Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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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...

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High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells

Cited by 55 publications

References 63 publications

Genetic changes associated with testicular cancer susceptibility

Genetic changes associated with testicular cancer susceptibility

Structural Dynamics of Lateral and Diagonal Loops of Human Telomeric G-Quadruplexes in Extended MD Simulations

Treating Cancer by Targeting Telomeres and Telomerase

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