Expression of the human telomerase reverse transcriptase gene is modulated by quadruplex formation in its first exon due to DNA methylation

Li, Pei-Tzu; Wang, Zifu; Chu, I-Te; Kuan, Yen-Min; Li, Minghao; Huang, Mu-Ching; Chiang, Pei-Chi; Chang, Ta‐Chau; Chen, Chin-Tin

doi:10.1074/jbc.m117.808022

Cited by 29 publications

(31 citation statements)

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“…Opposite observations were made in case of the CpG19 site, where methylation level was decreased in these anatomical sites. Similar results were obtained by Li et al (2017) after examining hTERT promoter methylation status in PBLs of recurrent and non-recurrent thyroid cancer (TC) patients. They observed that recurrence group showed significantly higher DNA methylation level compared to the non-recurrence cohort.…”

Section: Discussionsupporting

confidence: 70%

“…They observed that recurrence group showed significantly higher DNA methylation level compared to the non-recurrence cohort. Moreover, in the recurrence group, DNA methylation level was closely associated with tumor stage and lymph node metastasis of TC patients (Li et al 2017). According to de Wilde et al (2010), investigation of hTERT promoter methylation status in cervical cancer, shows hTERT hypermethylation in 100% of analyzed cancer specimens and 38% of the high-grade precursor lesions in contrast to normal tissues, where only 5% of which presented a positive methylation pattern (de Wilde et al 2010).…”

Section: Discussionmentioning

confidence: 99%

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hTERT promoter methylation status in peripheral blood leukocytes as a molecular marker of head and neck cancer progression

et al. 2018

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Cancer cells, including head and neck cancer cell carcinoma (HNSCC), are characterized by an increased telomerase activity. This enzymatic complex is active in approximately 80-90% of all malignancies, and is regulated by various factors, including methylation status of hTERT gene promoter. hTERT methylation pattern has been thoroughly studied so far. It was proved that hTERT is aberrantly methylated in tumor tissue versus healthy counterparts. However, such effect has not yet been investigated in PBLs (peripheral blood leukocytes) of cancer patients. The aim of this study was to analyze the hTERT gene promoter methylation status in blood leukocytes. DNA was extracted from PBL of 92 patients with histologically diagnosed HNSCC and 53 healthy controls. Methylation status of whole hTERT promoter fragment with independent analysis of each 19 CpG sites was performed using bisulfide conversion technique followed by sequencing of PCR products. Not significant (p = 0.0532) differences in the general frequency of hTERT CpG sites methylation were detected between patients and healthy controls. However, it was discovered that some of analyzed positions (CpG islands: 1 [p = 0.0235], 5 [p = 0.0462], 8 [p = 0.0343]) are significantly more often methylated in HNSCC patients than in controls. The opposite finding was observed in case of CpG position 2 (p = 0.0210). Furthermore, closer analysis of single CpG positions revealed differences in methylation status dependent on anatomical site and TNM classification. To conclude, hTERT promoter methylation status (general or single CpG sites) would be considered as a molecular markers of HNSCC diagnostics.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

hTERT promoter methylation status in peripheral blood leukocytes as a molecular marker of head and neck cancer progression

et al. 2018

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“…Consistent with this, stabilization of G-quadruplexes was noted to mask binding of the well-studied regulatory factors Sp1 and CTCF at the hTERT promoter 18,68,69 . From our results here, it is likely that 42 .…”

Section: Discussionsupporting

confidence: 58%

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Sharma

Mukherjee

Roy

et al. 2020

Preprint

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Tight regulatory mechanisms to maintain repression of human Telomerase (hTERT), the sole protein that synthesizes telomeres, is crucial for normal adult somatic cells. In contrast, enhanced telomerase activity and resulting pathological maintenance of telomeres, is widely understood as causal in >90% of human cancers. These implicate underlying mechanisms connecting hTERT regulation and telomeres, possibly through telomeric proteins, that remain unclear. In light of of recent work by us and others showing non-telomeric function of the telomere-binding protein TRF2, here we examined whether and how TRF2 affected hTERT regulation. Direct binding of TRF2spanning ~450 bp of the hTERT promoter from the Transcriptional Start Site (TSS)led to TRF2-dependent recruitment of the polycomb repressor complex PRC2 in both normal and cancer cells. This induced repressor histone modifications resulting in TRF2-dependent hTERT repression.Mutations in the hTERT promoter, found frequently in aggressive glioblastoma and reported to destabilize the G-quadruplex structure, resulted in loss of TRF2 binding and consequent hTERT over-expression. Conversely, using G-quadruplex-stabilizing ligands we regained TRF2 binding, hTERT re-suppression, in highly proliferating glioblastoma cells with telomerase hyperactivation due to hTERT promoter mutations. Together, results herein demonstrate direct control of hTERT through TRF2 in a G-quadruplex-dependent mannerimplicating mechanisms of how telomerase regulation might be linked to telomeres in normal and cancer cells. IntroductionTelomeres, comprising of (GGGTTA) n repeats in complex with telomere-binding proteins, at the end of human chromosomes are essential for genome stability 1-6 . The only protein that can replicate telomeric DNA is telomerase -a ribonucleoprotein complex of the reverse transcriptase (hTERT) and RNA the template (hTERC). In adult somatic cells, hTERT is kept trasncriptionally repressed.Resulting loss of telomeres with each replication cycle leads to replicative senescence, much like a 'molecular clock' that helps maintain cellular homeostasis. Deregulation or loss of hTERT repression, which results in aberrant maintenance of telomeres, has been causally associated to initiation/progression of more than 90% human cancers 7,8 . Although, these suggest tight control of telomerase might be linked to telomeres -the role of telomeres or telomere-binding factors in regulation of hTERT remains poorly explored.Relatively recent work by others and us showing non-telomeric binding of telomere-binding proteins, TRF1, TRF2 and RAP1, is of interest in this context. Genome wide RAP1 association has been reported in mouse and human cells while TRF1/TRF2 binding has been demonstrated in human cells 9-11 . Notably, we found about 20000 TRF2 binding sites spread throughout the genome where TRF2-mediated promoter epigenetics and gene regulation was evident. A large fraction of the TRF2 binding sites coincided with potential DNA secondary structure G-quadruplex-forming sequences 12 .Further, ...

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“…Conversely, DNA methylation can influence G4 topology [85] and may modulate binding by other G4-associated proteins. For instance, CpG methylation at the hTERT gene promoter was suggested to induce G4 formation, resulting in displacement of the CCCTC-binding factor (CTCF) and elevated transcription [86].…”

Section: Natural G4-binding Proteinsmentioning

confidence: 99%

The Structure and Function of DNA G-Quadruplexes

Spiegel

Adhikari

Balasubramanian

2020

Trends in Chemistry

590

568

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Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery. Beyond the DNA Double HelixA chemist's perspective on the function of a molecule, or a system of molecules, is typically led by a consideration of how molecular structure dictates function. The most widely recognised DNA structure is that of the classical DNA double helix [1], which defines a structural basis for the genetic code via defined base-pairing. Yet, it is evident that DNA is structurally dynamic and capable of adopting alternative secondary structures. One such class of DNA secondary structure is the four-stranded Gquadruplex (G4). Herein, we discuss some of the key scientific history that has shaped our understanding of this structural motif, its probable functions in biology, and major unanswered questions that remain to be solved.

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Expression of the human telomerase reverse transcriptase gene is modulated by quadruplex formation in its first exon due to DNA methylation

Cited by 29 publications

References 52 publications

hTERT promoter methylation status in peripheral blood leukocytes as a molecular marker of head and neck cancer progression

hTERT promoter methylation status in peripheral blood leukocytes as a molecular marker of head and neck cancer progression

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

The Structure and Function of DNA G-Quadruplexes

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