Telomerase enzymatic component hTERT shortens long telomeres in human cells

Zheng, Yun‐Ling; Zhang, Fan; Sun, Bing; Du, Juan; Sun, Chongkui; Yuan, Jie; Wang, Ying; Tao, Lian; Kota, Krishna Kiran; Li, Xuefeng; Schlegel, Richard; Yang, Qin

doi:10.4161/cc.28705

Cited by 22 publications

(24 citation statements)

References 57 publications

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“…Recent studies have linked abnormally long telomeres to tumorigenesis [6, 8, 56–59]. Interestingly, both FANCD2 and SLX4 localize to telomeres and are required for maintaining long telomeres in ALT cells.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of telomere maintenance such as defective length homeostasis (leading to critical shortening or over-lengthening), loss in protective function of shelterin proteins, and other defects in telomere biology leads to ATM/ATR kinase-involved DNA damage response or delays in DNA replication, resulting in genome instability, cell proliferation defects, cellular senescence or cell apoptosis (Figure 1A) [5, 6]. In humans, telomere attrition is associated with replicative cell senescence in culture, ageing populations, and environmental and lifestyle factors that contribute to ageing and ageing-related diseases.…”

Section: Introductionmentioning

confidence: 99%

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Fanconi anemia proteins in telomere maintenance

Sarkar

Liu

2016

DNA Repair

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Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fanconi anemia proteins in telomere maintenance

Sarkar

Liu

2016

DNA Repair

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“…This shelterin protein unsaturation or “intermediate status” of telomeres resulted in impaired chromosome end protections that are susceptible to DNA damage response, leading to genomic instability (32). Recent data by our group demonstrated that telomerase, a key telomere maintenance enzyme, not only elongates short telomeres, but also shortens excessively long telomeres in human cells, indicating maintaining telomere homeostasis is critical for a normal cellular function (22). TLV, as defined in the present study, measures the combined effects of very short and excessively long telomeres and represents a novel aspect of telomere function and might be a useful biomarker for cancer risk.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of human cancer cell lines and knockout mouse strains have shown that the shortest telomeres, not average telomere length, drove chromosome instability in cancer cells, and chromosomal arms possessing the shortest telomeres were more often found in telomere fusions, leading to chromosomal abnormality (19–21). Our recent data showed that telomerase, the key telomere maintenance enzyme, not only elongates short telomeres, but also shortens excessively long telomeres in normal and cancerous human cells (22). These dual functions of telomerase indicate that keeping an optimal telomere length for each chromosomal end is a critical aspect of telomere maintenance and may be important for the protection of the genome.…”

Section: Introductionmentioning

confidence: 99%

Telomere length variation: A potential new telomere biomarker for lung cancer risk

et al. 2015

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Objectives In this report the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk were examined. Materials and Methods The study design is case-control. Cases (N = 191) were patients newly diagnosed with histologically confirmed non-small cell lung cancer. Controls (N = 207) were healthy individuals recruited from the same counties as cases and matched to cases on age and gender. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk. Results Telomere length variation across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46 – 14.9] and 0.46 (95% CI: 0.25 – 0.84) for younger (age ≤ 60) and older (age > 60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% CI: 1.71 – 39.5) and 0.33 (95% CI: 0.15 – 0.72) for younger and older individuals, respectively. Conclusions TLV in blood lymphocytes is significantly associated with lung cancer risk and the associations were modulated by age. TLV in combination with mean telomere length might be useful in identifying high risk population for lung cancer computerized tomography screening.

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“…Telomere consists of 6 nucleotide sequences (GGATTT) at the terminal region of the eukaryotic chromosomes. During chromosome replication, DNA polymerase cannot replicate the ends of chromosomes at somatic level, and gradual loss of telomeres occurs after each round of replication [1][2][3]. Somatic cells have a limited capacity for proliferation known as the Hayflick limit, which is due to this loss of chromosome ends, and the number of replication beyond this limitation leads to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Biological and Molecular Diversity in Telomerase: Characteristics of hTERT in Human, Vertebrates and Yeast

Abdollahi¹,

Mehdipour²

2016

Cell Dev Biol

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hTERT (human telomerase reverse transcriptase) is the catalytic subunit of telomerase enzyme, and is essential for its functions. The aim of this review was to compare the TERT in human and other species including microorganism, vertebrates and mammals, in terms of its functions and regulation. According to literature, the catalytic subunit of telomerase in animals contains many conserved domains and residues, which have crucial roles in its functions. Moreover, the structure and biology of human telomerase seem to be more similar to that of dog compared other animals. Thus interestingly, unlike the mouse that is seemingly not a proper model for evaluation of telomerase activity and its regulation, dog may be an appropriate model for the experimental investigations of telomerase function and therapeutic strategies in cancer studies.

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Telomerase enzymatic component hTERT shortens long telomeres in human cells

Cited by 22 publications

References 57 publications

Fanconi anemia proteins in telomere maintenance

Fanconi anemia proteins in telomere maintenance

Telomere length variation: A potential new telomere biomarker for lung cancer risk

Biological and Molecular Diversity in Telomerase: Characteristics of hTERT in Human, Vertebrates and Yeast

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