As an important telomere binding protein, TPP1 protects the ends of telomeres and maintains the stability and integrity of its structure and function by interacting with other five essential core proteins (POT1, TRF1, TRF2, TIN2, and RAP1) to form a complex called Shelterin. Recently, researchers have discovered that TPP1 participates in protection of telomeres and regulation of telomerase activity. The relationship between TPP1 and tumorigenesis, tumor progression and treatment has also been investigated. This paper reviews the latest findings of TPP1 regarding to its structure, function and interaction with other proteins involved in tumorigenesis.
Chromosomal Instability ; DNA Damage ; Humans ; Neoplasms ; genetics ; Telomere ; Telomere-Binding Proteins ; chemistry ; physiology

Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase maintenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To investigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 + 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potassium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformational changes and targeted drug design.
Binding Sites ; G-Quadruplexes ; Humans ; Molecular Dynamics Simulation ; Movement ; Potassium ; metabolism ; Principal Component Analysis ; Substrate Specificity ; Telomere ; chemistry ; metabolism ; Thermodynamics

Distal 15q trisomy or tetrasomy is associated with a characteristic phenotype that includes mild to moderate intellectual disability, abnormal behavior, speech impairment, overgrowth, hyperlaxity, long face, prominent nose, puffy cheeks, pointed chin, small ears, and hand anomalies (mainly arachno- and camptodactyly). We present the case of a 13-yr-old girl with the main clinical features of 15q overgrowth syndrome and a 46,XX,dup(15)(q24q26.3)[117]/46,XX[3].ish dup(15)(q24q26.3) (SNPRN+,PML+,subtel++,tel++) de novo karyotype. The findings in this case are consistent with those in the previous distal 15q trisomy cases that presented with overgrowth and mental retardation. Further, the rearranged chromosome had a double set of directly oriented telomeric and subtelomeric sequences.
Adolescent ; *Chromosome Aberrations ; *Chromosomes, Human, Pair 15 ; Female ; Growth Disorders/diagnosis/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Mental Retardation/diagnosis/*genetics ; Syndrome ; Telomere/*chemistry

The detection of sperm DNA damage, as an important supplement to semen routine examination strategies, has been applied in some clinical andrology laboratories. What factors may lead to sperm DNA damage remains one of the concerns among many andrologists. Present studies show a variety of factors of sperm DNA damage, including age, environmental pollutants such as organophosphorus and organochloride pesticides, plasticizer, heavy metals such as lead, carcinogens such as polycyclic aromatic hydrocarbons (c-PAHs) and zearalenone (ZEA), male reproductive system diseases or systemic diseases such as varicocele, infection, tumor, spermatogenesis and maturation dysfunction, spinal cord injury and endocrine disorders, seasons and temperature, lifestyle, abstinence time, semen refrigeration, semen handling in vitro, and certain medications. Among them, spermatogenesis and sperm maturation dysfunction may be the most secretive factors, which are involved in the molecular mechanisms of sperm chromatin packaging and restructuring, such as the transformation of histone to protamine, single nucleotide polymorphism of genes, and the role of telomere, which may be one of the hotspots in the future studies of sperm DNA damage. Relevant researches in the future are expected to focus on the prevention of sperm DNA damage and clarification of its specific pathogenic mechanisms so as to provide some evidence for its treatment.
Age Factors ; Chromatin ; chemistry ; DNA Damage ; Environmental Pollutants ; toxicity ; Humans ; Male ; Protamines ; Semen ; drug effects ; Specimen Handling ; Spermatogenesis ; Spermatozoa ; drug effects ; Telomere ; physiology ; Varicocele ; complications

This study was aimed to investigate the modulating effects on telomere length and telomerase activity in K562 cells treated by arsenic trioxide, ginseng saponin, beta-elemene alone or in combination with cyclophosphamide (CTX) and to explore the possible mechanism and new therapy for acute leukemia. Human erythroleukemic cell line K562 was co-cultured with the above-mentioned drugs. Cells were collected after 24, 48 and 72 hours for further detection. Telomere length and telomerase activity were detected by Southern-blot and PCR-ELISA respectively. The effects of these drugs were observed at different concentrations and exposure time. The results showed that (1) ginseng saponin, arsenic trioxide, beta-elemene, or CTX could completely inhibit the telomerase activity of K562 cells at proper concentrations and exposure time. The inhibiting effects were enhanced when the three former drugs were used with CTX. Telomerase activity decreased proportionally with the concentrations and length of time. (2) viability of K562 cells was decreased after being co-cultured with arsenic trioxide, ginseng saponin, beta-elemene and CTX. The level of inhibition depends on the concentration and exposure time. (3) telomere length of K562 cells was 5.36 +/- 0.18 kb. After being co-cultured with those drugs for 72 hours, telomere length was 5.90 kb -6.50 kb, significantly longer than that of control (5.18 - 5.35 kb). It is concluded that arsenic trioxide, ginseng saponin, and beta-elemene can inhibit the growth and telomerase activity of K562 cells. The inhibiting effects were enhanced when they were used in combination with CTX. The depression of telomerase activity may be one of the mechanisms of anti-tumor effect. Less dosage and shorter course can be expected when arsenic trioxide, ginseng saponin, and beta-elemene are used in combination with CTX. When telomerase activity was depressed, the telomere length prolonged a little, indicating K562 cell line may extend telomeres by some alternative way other than telomerase activation.
Arsenicals ; pharmacology ; Cyclophosphamide ; pharmacology ; Drug Synergism ; Humans ; K562 Cells ; Oxides ; pharmacology ; Panax ; chemistry ; Saponins ; pharmacology ; Sesquiterpenes ; pharmacology ; Telomerase ; drug effects ; metabolism ; Telomere ; drug effects

Objective: To analyze the contribution and interaction of polycyclic aromatic hydrocarbons (PAH)-DNA adducts and changes of telomere length (TL) on missed abortion. Methods: From March to December 2019, patients with missed abortion in the First Hospital of Shanxi Medical University and pregnant women with normal pregnancy but voluntary abortion in the same department during the same period were selected and divided into a case group and a control group. Questionnaire was used to investigate the general situation and the pregnancy situation of the subjects. The abortion villi were collected and the content of PAH-DNA adducts and TL was detected. Logistic regression model was used to analyze the associated factors of missed abortion. R epiR package and Mediation package were used to analyze the effect and relationship between PAH-DNA adducts and TL on missed abortion. Results: The age of the subjects was(29.92±5.69)years old. The M(Q₁,Q₃)of PAH-DNA adducts was 453.75(404.61, 504.72) pg/ml. The M(Q₁,Q₃)of TL was 1.21(0.77, 1.72). The content of PAH-DNA adducts in the case group was higher than that in the control group (Z=-2.10, P=0.036), while the TL was lower than that in the control group (Z=-4.05, P<0.001). Multivariate logistic regression showed that low, medium and high levels of PAH-DNA adducts (OR=3.17,95%CI:1.41-7.14;OR=2.85,95%CI:1.25-6.52;OR=2.46,95%CI:1.07-5.64), and long, medium and short levels of TL (OR=2.50,95%CI:1.11-5.63;OR=3.32,95%CI:1.45-7.56;OR=3.22,95%CI:1.42-7.26) were all risk factors for missed abortion. The medium level of PAH-DNA adducts had a 2.76-fold higher risk of shortened TL than those with the lowest level, and no mediating role of TL was found. The stratified analysis showed that when the TL level was longer (>1.21), the low and high levels of PAH-DNA adducts were associated with missed abortion (all P<0.05); when the TL level was shorter (<1.21), the medium level of PAH-DNA adducts was associated with abortion (P=0.025). At lower levels of PAH-DNA adducts, no effect of TL on missed abortion was observed, while, at higher levels, TL was strongly associated with missed abortion (OR=7.50,95%CI:1.95-28.82;OR=6.04,95%CI:1.54-23.65;OR=9.05,95%CI:2.34-35.04). The interaction analysis found that the AP was 0.72 (95%CI: 0.46-0.99), and the SI was 5.21 (95%CI: 2.30-11.77). Conclusion: The high level of PAH-DNA adducts and shortened TL may increase the risk of missed abortion, and there may be a positive additive interaction between the two factors on missed abortion.
Humans ; Female ; Pregnancy ; Young Adult ; Adult ; DNA Adducts ; Abortion, Missed/chemically induced* ; Polycyclic Aromatic Hydrocarbons ; Abortion, Spontaneous/chemically induced* ; Telomere/chemistry*

Telomeres are the ends of the linear chromosomes of eukaryotes and consist of tandem GT-rich repeats in telomere sequence i.e. 500-3000 repeats of 5'-TTAGGG-3' in human somatic cells, which are shortened gradually with age. The G-rich overhang of telomere sequence can adopt different intramolecular fold-backs and tetra-stranded DNA structures, in vitro, which inhibit telomerase activity. In this report, DNA binding agents to telomere sequence were studied novel therapeutic possibility to destabilize telomeric DNA sequences. Oligonucleotides containing the guanine repeats in human telomere sequence were synthesized and used for screening potential antitumor drugs. Telomeric DNA sequence was characterized using spectral measurements and CD spectroscopy. CD spectrum indicated that the double-stranded telomeric DNA is in a right-handed conformation. Polyacrylamide gel electrophoresis was performed for binding behaviors of antitumor compounds with telomeric DNA sequence. Drugs interacted with DNA sequence caused changes in the electrophoretic mobility and band intensity of the gels. Depending on the binding mode of the anticancer drugs, telomeric DNA sequence was differently recognized and the efficiency of cleavage of DNA varies in the bleomycin-treated samples under different conditions. DNA cleavage occurred at about 1% by the increments of 1 mM bleomycin-Fe(III). These results imply that the stability of human telomere sequence is important in conjunction with the cancer treatment and aging process.
Antineoplastic Agents/*metabolism ; Bleomycin/metabolism/pharmacology ; Circular Dichroism ; Comparative Study ; DNA/chemistry/drug effects/*metabolism ; DNA Damage ; Dactinomycin/metabolism ; Doxorubicin/*analogs & derivatives/metabolism ; Human ; Nogalamycin/metabolism ; Nucleic Acid Conformation ; *Repetitive Sequences, Nucleic Acid ; Telomere/drug effects/*genetics

This study was aimed to explore the prognostic significance of telomere length in patients with chronic lymphocytic leukemia (CLL) and to analyze relation of telomere length with Binet stage, IgVH mutation status, CD38, ZAP-70 expression as well as other clinical features. 35 CLL patients who contained 80% or more tumor cells in the peripheral blood or bone marrow samples were selected as objects studied, while 13 healthy donors were served as normal controls. The telomere relative length was detected by using a real-time fluorescent quantitative polymerase chain reaction method (qPCR); the expression of CD38 and ZAP-70 protein were detected by flow cytometry, the IgVH mutation was detected by multiplex PCR. The results showed that the mean telomere relative length in CLL patients and normal controls were 0.384 and 0.443 respectively, but the difference between them was not significant (p > 0.05). The telomere length was significantly correlated with Binet stages and IgVH mutation status. Patients in Binet stage B and C showed significantly shorter telomeres than those in Binet stage A (p = 0.001). Mean telomere relative lengths in patients without IgVH mutation were shorter than those in patients with IgVH mutation (p = 0.015). No relation of telomere length with sex, age, ZAP-70 protein and CD38 were found (p > 0.05). It is concluded that telomere length may have a prognostic significance for CLL patients. Combining telomere length and IgVH mutation status may achieve a better prognostic subclassification for CLL patients.
ADP-ribosyl Cyclase 1 ; metabolism ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; genetics ; metabolism ; Male ; Middle Aged ; Mutation ; Prognosis ; Telomere ; chemistry ; genetics ; metabolism ; ZAP-70 Protein-Tyrosine Kinase ; metabolism

OBJECTIVETo study the effects of Cynomorium songaricum polysaccharide (CSP) on telomere length in blood and brain tissues of aged mice in order to provide some evidence for CSP's development and applying in the clinical uses.

METHODKunming mice were intraperitoneal injected D-galactose (500 mg x kg(-1) x d(-1)) to make the aging models, and different dosages of CSP (20, 40, 80 mg x kg(-1)) were given by gavage for 56 days. The average length of telomere was determined by real-time fluorescence quantitative PCR.

RESULTThe relative T/S ratio of the group high and middle dosages of CSP in blood were 1.64 +/- 0.36 and 1.33 +/0.28, respectively, and higher than that of the group of senescence 1.01 +/- 0.13 (P < 0.01). Values of the group of high, middle, and low dosages of CSP in brain tissues were 3.34 +/- 0.58, 2.30 +/- 0. 75 and 1.55 +/- 0.58, respectively, and significantly higher than that of the group of senescence 1.04 +/- 0.33 (P < 0.01).

CONCLUSIONCSP can exert the anti-aging effects by increase telomere length f senescence mice.

Aging ; drug effects ; Animals ; Animals, Newborn ; Brain ; drug effects ; pathology ; Cellular Senescence ; drug effects ; Cynomorium ; chemistry ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Galactose ; pharmacology ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; Polysaccharides ; pharmacology ; therapeutic use ; Telomere ; drug effects ; physiology

OBJECTIVETo investigate the mechanism of senescence delay of human diploid fibroblast (2BS) and protecting telomere length by epimedium flavonoids (EF).

METHODSThe drug sera of EF were used to treat the 2BS. The population doublings of 2BS cells were observed, the mRNA expression of p16 gene were determined by fluorescence real-time quantitative RT-PCR, the telomerase activation of 2BS cells were determined by TRAP-Hyb, the total retinoblastoma (Rb) and phosphorated Rb protein content were detected by ELISA, the telomere length of 2BS cells were determined by telomere restriction fragment (TRF) Southern blot assay.

RESULTSEF could significantly extend the population doublings of 2BS cells, the expression of p16 mRNA was decreased and the content of phosphorated Rb protein were increased by EF. The telomere lengthening of 2BS cells were improved by EF, but the telomerase was not activated.

CONCLUSIONIn senescence human fibroblasts 2BS cells, p16 gene mRNA expression increased, content of phosphorated Rb protein decreased and the telomere length of 2BS shortened, EF might delay the aging of cells through inhibiting the p16 gene expression, promoting the production of phosphorated Rb protein and to protect the length of telomere, but not activating the telomerase.

Animals ; Cells, Cultured ; Cellular Senescence ; genetics ; Cyclin-Dependent Kinase Inhibitor p16 ; biosynthesis ; genetics ; Epimedium ; chemistry ; Fibroblasts ; cytology ; Flavonoids ; pharmacology ; Male ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Sprague-Dawley ; Retinoblastoma Protein ; metabolism ; Telomerase ; biosynthesis ; Telomere ; genetics ; metabolism ; Transduction, Genetic