Telomeric Associations Research Articles

Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study

BackgroundBiologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.MethodsThis pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks’ gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.Results156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).ConclusionOur exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.

Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.

Spectroscopy evidence of interaction of 1,5 disubstituted piperidino-amido anthraquinone derivative with human telomeric G-quadruplex DNA: Basis of anticancer action

The binding of ligands to G-quadruplex (G4) structures at the ends of human telomeric DNA induces thermal stabilization, which interferes with telomere maintenance by disrupting the association of telomeres with the telomerase enzyme—an important marker for cancer. Understanding the binding mode of the ligand-G quadruplex DNA complex is imperative for evaluating the relative efficacy and specificity of their interaction. We focused on the interaction of 1,5-Bis(3-piperidino propionamido) anthracene-9,10-dione with human telomeric DNA sequences using surface plasmon resonance, absorbance, fluorescence (steady-state and lifetime), and circular dichroism spectroscopy techniques. The ligand binding with HTel22 (Kb = 8.4 × 105 M−1) induced cell toxicity with an IC50 value of ∼ 8.64 µM in MCF-7 cancer cell lines. Significant hypochromism (59 %), fluorescence quenching (97 %), no change in fluorescence lifetime and absence of induced Circular Dichroism (CD) band upon addition of G4 DNA to ligand, suggest a groove/external binding mode. CD spectral changes reflect rearrangement in parallel and antiparallel strands to accommodate the ligand. Docking results reveal specific short contacts of the ligand's side chain, including 9CO, 13N, 14NH, and 11CO, with the grooves of the G4 DNA, without making any contact with the loops, favoring an energetically more favorable conformation. Thermal denaturation profiles, obtained by Differential Scanning Calorimetry and CD, show the stabilization of wHTel26 and HTel22 G4 DNA in K+ and Na+ rich solutions by 21.2 and 17.6 °C, respectively, which may restrict the access of telomerase to telomeres. The findings indicate the potential of modifying anthraquinone substituent groups for therapeutic applications.

Chromosomal aberrations induced by Mitomycin C in canine lymphocytes

Chromosomal aberrations comprise an abnormal number of chromosomes as well as changes in the structure of the chromosomes. Aberrations in the structure of chromosomes, such as gaps and breaks in chromatids and chromosomes, acentric fragments, telomeric associations, deletions, early chromatid-separation and large scale effects, such as pulverized metaphases, and sticky metaphases. In this study, the effect of Mitomycin C, a recognized clastogen on human lymphocytes, was assayed in cultures of canine lymphocytes, an animal species that is flourishing in comparative medicine. Blood cultures were performed on samples from a male and a female dog. Cytotoxicity using the mitotic index and genotoxicity testing were performed with 0.25 µg/ml Mitomycin C. The total chromosomal aberrations were significantly higher due to the effect of Mitomycin C (P=0.0247). The number of chromatid breaks nearly quintupled, while pulverized metaphases were found to be six times more frequent, and endoduplicated cells were three times higher than in negative control cultures. The quantitatively most relevant chromosomal aberration was the presence of sticky metaphases, related to adverse effects in chromatin proteins. The potential use of canine lymphocytes for chromosomal aberration assay is emphasized in the evaluation or re-evaluation of the genotoxic in vitro effect of xenobiotics, to evidence chromosomal damage.

A Novel Role of Prostate-Specific Membrane Antigen in Telomere Stability in Prostate Cancer Cells.

Role of PSMA in telomere stability suggests a strong correlation between PSMA expression and prostate cancer progression.

Enzymatic approaches against SARS-CoV-2 infection with an emphasis on the telomere-associated enzymes.

The pandemic phase of coronavirus disease 2019 (COVID-19) appears to be over in most countries. However, the unexpected behaviour and unstable nature of coronaviruses, including temporary hiatuses, re-emergence, emergence of new variants, and changing outbreak epicentres during the COVID-19 pandemic, have been frequently reported. The mentioned trend shows the fact that in addition to vaccine development, different strategies should be considered to deal effectively with this disease, in long term. In this regard, the role of enzymes in regulating immune responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently attracted much attention. Moreover, several reports confirm the association of short telomeres with sever COVID-19 symptoms. This review highlights the role of several enzymes involved in telomere length (TL) regulation and explains their relevance to SARS-CoV-2 infection. Apparently, inhibition of telomere shortening (TS) through inhibition and/or activation of these enzymes could be a potential target in the treatment of COVID-19, which may also lead to a reduction in disease severity.

TRF1 uses a noncanonical function of TFIIH to promote telomere replication.

Telomeric DNA challenges the replisome and requires TRF1 for efficient duplication. TRF1 recruits the BLM helicase, but BLM loss does not explain the extensive telomere fragility, ATR signaling, and sister telomere associations (STAs) induced by TRF1 deletion. Here, we document that Helix2 of the TRFH domain and Helix1 of the Myb domain of TRF1 are required for efficient telomere replication. Mutation of both helices generated a TRF1 separation-of-function mutant (TRF1-E83K/LW-TI) that induced severe telomere replication defects but no ATR signaling or STAs. We identified the transcription and nucleotide excision repair (NER) factor TFIIH as a critical effector of TRF1. Loss of TFIIH subunits, but no other NER factors, caused the same telomere replication phenotypes as the TRF1-E83K/LW-TI mutant independent of the effects on TRF1 expression. TFIIH subunits coimmunoprecipitated with wild-type TRF1 but not with TRF1-E83K/LW-TI. These results establish that the major mechanism by which TRF1 ensures telomere replication involves a noncanonical function of TFIIH.

Changes in Telomere Length and Indicators of Oxidative Stress in Critically Ill Mechanically Ventilated Adults - A Pilot Study.

Telomeres are structures at the end of chromosomes that shorten with each cell division. The purpose of this pilot project is to report changes in telomere length (T/S ratio), indicators of oxidative stress (serum protein carbonyl, vitamin C, GSH:GSSG, and total antioxidant capacity) from Intensive Care Unit (ICU) admission to ICU discharge, and to explore their association with ICU-related morbidities among critically ill mechanically ventilated adults. Blood was collected from mechanically ventilated patients (n = 25) at enrollment and within 48 hours of ICU discharge. Telomere length from peripheral blood mononuclear cells (PBMCs) was determined using RTqPCR. ELISAs were used to measure indicators of oxidative stress. Descriptive analysis, paired t-tests, and Pearson's correlations were performed. Mean age was 62.0 ± 12.3years, 28.6% were male, and 76.2% were White with disease severity using APACHE III (74.6 ± 24.6) and SOFA (7.6 ± 3.2). Mean T/S ratios shortened (ICU: 0.712, post-ICU: 0.683, p < 0.001, n = 19) and serum protein carbonyl increased (ICU: 7437nmol/mg ± 3328, post-ICU: 10,254nmol/mg ± 3962, p < 0.005) as did the oxidative stress index (protein carbonyl/GSH:GSSG, ICU: 1049.972 ± 420.923, post-ICU: 1348.971 ± 417.175, p = 0.0104). T/S ratio was positively associated with APACHE III scores (ICU: r = 0.474, post-ICU: r = 0.628, p < 0.05). Pilot findings suggest that critical illness significantly correlates with telomere attrition, perhaps due to increased oxidative stress. Future larger and longitudinal studies investigating mechanisms of telomere attrition and associations with clinical outcomes are needed to identify potential modifiable factors for subsequent intervention to improve outcomes for critically ill patients.

Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility.

Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. All these single nucleotide polymorphisms were further analyzed and only 11 SNPs (W8R, G25R, P649A, I624T, C618R, F607V, S604G, C592Y, C592R, G187W, and R53C) were found to be the most damaging by at least six software tools and exert deleterious effect on the TERB1, TERB2, and MAJIN protein structures and likely functions. They revealed high conservation, less stability, and having a role in posttranslational modifications. This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility.

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae.

Rap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. tlc1-tm cells grow similar to wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. Rif2 is a protein normally recruited to telomeres by Rap1, but we show that Rif2 can still associate with Rap1-depleted tlc1-tm telomeres, and that this association is required to inhibit telomere degradation by the MRX complex. Rif2 and the Ku complex work in parallel to prevent tlc1-tm telomere degradation; tlc1-tm cells lacking Rif2 and the Ku complex are inviable. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.

Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis.

Simple SummaryThe overall clinical and cell biological behaviour of giant cell tumour of bone still remains very difficult to understand. This entity is a prototype neoplasm illustrating that the scientific work around nucleosome mutations in cancer is a hot topic. This review tries to summarise and integrate the wide spread insights in this research era with specific attention to the cell biological aspects of giant cell tumour of bone with the focus on genomic and epigenomic alterations that may lead to genomic instability and malignancy. Moreover, the ultimate goal is to connect all major characteristics of this tumour to a comprehensive understanding, like parts of a broad etiogenic puzzle, which may lead to new insights.Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung ‘plugs’). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many ‘old’ questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB.

Short telomeres and severe COVID-19: The connection conundrum.

The exponential rise of COVID-19 mortality among older adults has been rightly attributed to a declining immunity with age. Still, for unknown reasons, older adults are far more likely to die from COVID-19 than from the seasonal influenza, and this puzzle demands specific answers. One of them emerges from the telomere study by Wang et al [1]. Other small studies [2,3], each less than 100 participants, have also observed association of short hematopoietic cell telomeres with severe COVID-19. Wang's study, in contrast, consists of 6,775 adults with COVID-19.

A Turner syndrome case associated with dic(Y;22)

BackgroundConstitutional telomeric associations are very rare events and the mechanism underlying their development is not well understood.Case presentationWe here describe a female case of Turner syndrome with a 45,X,add(22)(p11.2)[25]/45,X[5]. We reconfirmed this karyotype by FISH analysis as 45,X,dic(Y;22)(p11.3;p11.2)[28]/45,X[2].ish dic(Y;22)(SRY+,DYZ1+). A possible mechanism underlying this mosaicism was a loss of dic(Y;22) followed by a monosomy rescue of chromosome 22. However, SNP microarray analysis revealed no loss of heterozygosity (LOH) in chromosome 22, although a mosaic pattern of LOH was clearly detectable at the pseudoautosomal regions of the sex chromosomes.ConclusionsOur results suggest that the separation of the dicentric chromosome at the junction resulted in a loss of chromosome Y without a loss of chromosome 22, leading to this patient’s unique mosaicism. Although telomere signals were not detected by FISH at the junction, it is likely that the original dic(Y;22) chromosome was generated by unstable telomeric associations. We propose a novel “pulled apart” mechanism as the process underlying this mosaicism.

The SUN1-SPDYA interaction plays an essential role in meiosis prophase I

Chromosomes pair and synapse with their homologous partners to segregate correctly at the first meiotic division. Association of telomeres with the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex composed of SUN1 and KASH5 enables telomere-led chromosome movements and telomere bouquet formation, facilitating precise pairwise alignment of homologs. Here, we identify a direct interaction between SUN1 and Speedy A (SPDYA) and determine the crystal structure of human SUN1-SPDYA-CDK2 ternary complex. Analysis of meiosis prophase I process in SPDYA-binding-deficient SUN1 mutant mice reveals that the SUN1-SPDYA interaction is required for the telomere-LINC complex connection and the assembly of a ring-shaped telomere supramolecular architecture at the nuclear envelope, which is critical for efficient homologous pairing and synapsis. Overall, our results provide structural insights into meiotic telomere structure that is essential for meiotic prophase I progression.

Lung Transplant Recipients with Idiopathic Pulmonary Fibrosis and Telomere Dysfunction Have Impaired Donor-Specific Immune Responses

Purpose Telomere dysfunction is linked to idiopathic pulmonary fibrosis (IPF) and worse outcomes following lung transplantation. The association of telomere dysfunction with both CMV infection and leukopenia post-transplant suggests impaired immunity, but telomere associations with allograft-specific immune responses are unknown. We hypothesized that impaired proliferation to donor antigens would be associated with both IPF as a transplant indication and decreased telomere length. Methods We analyzed peripheral blood mononuclear cells (PBMC) from 14 IPF lung transplant recipients, and 12 age-matched non-IPF controls, before and 24 months after transplantation, as well as PBMC from 9 healthy donors. The proportions of regulatory, CD4+ conventional, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells (sBc) were quantified by flow cytometry. Proliferation was compared between IPF and non-IPF recipients by t-test. PBMC telomere length was measured by quantitative PCR and compared with proliferation to alloantigens by Pearson correlation. Results Pre-transplant, IPF lung transplant recipients demonstrated impaired CD8+ T cell proliferation to donor antigens, relative to non-IPF patients (P Conclusion IPF as an indication for lung transplant is associated with short leukocyte telomere length and impaired T cell responses to donor antigens. However, the rescue of proliferation by cytokine exposure suggests that infection could drive heterologous immunity and ensuing allograft dysfunction in this population. These findings may inform studies to optimize immunosuppression for lung transplant recipients with short telomeres.

Drosophila telomere capping protein HOAP interacts with DSB sensor proteins Mre11 and Nbs.

In eukaryotes, specific DNA-protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex. This capping complex is essential for the inhibition of the DNA damage response (DDR) at telomeres and contributes to genome integrity. In Drosophila, the central factors of telomere capping complex are HOAP and HipHop. Furthermore, a DDR protein complex Mre11-Rad50-Nbs (MRN) is known to be important for the telomere association of HOAP and HipHop. However, whether MRN interacts with HOAP and HipHop, and the telomere recognition mechanisms of HOAP and HipHop are poorly understood. Here, we show that Nbs interacts with Mre11 and transports the Mre11-Rad50 complex from the cytoplasm to the nucleus. In addition, we report that HOAP interacts with both Mre11 and Nbs. The N-terminal region of HOAP is essential for its co-localization with HipHop. Finally, we reveal that Nbs interacts with the N-terminal region of HOAP.

Human shelterin protein POT1 prevents severe telomere instability induced by homology-directed DNA repair.

The evolutionarily conserved POT1 protein binds single-stranded G-rich telomeric DNA and has been implicated in contributing to telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics, discovering that a complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies in human cells. Conditional deletion of POT1 in HEK293E cells gives rise to rapid telomere elongation and length heterogeneity, branched telomeric DNA structures, telomeric R-loops, and telomere fragility. We determine the telomeric proteome upon POT1-loss, implementing an improved telomeric chromatin isolation protocol. We identify a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon POT1-loss. Inactivation of the homology-directed repair machinery suppresses POT1-loss-mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology-directed repair.

RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops.

Telomeres which are present at the ends of eukaryotic chromosomes mediate genome stability and determine cellular lifespan1. Telomeric repeat containing RNAs (TERRA) are long noncoding RNAs transcribed from chromosome ends2,3, which regulate telomeric chromatin structure and telomere maintenance via telomerase and homology directed repair (HDR)4,5. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system to dissect the underlying mechanisms and demonstrate that the UUAGGG-repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA:RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation triggers telomere fragility and is promoted by the RAD51 recombinase and its interacting partner BRCA2 but counteracted by RNA surveillance factors, RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyzes R-loop formation with TERRA in vitro supporting a direct involvement of this DNA recombinase in TERRA recruitment by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA mediated R-loop formation post transcription providing a mechanism of how lncRNAs can be recruited to new loci in trans.

Evaluation of bovine sperm telomere length and association with semen quality

The study aimed to evaluate if the sperm telomere length can be considered as a new biomarker for sperm quality in bulls. Sperm Telomere Length was evaluated by Monochrome Multiplex Quantitative PCR in group A (n = 8) and group B (n = 8) bulls, classified according to standard semen analysis. Also, this parameter was measured before and after Percoll gradient separation within bulls that produced semen of satisfactory quality. Sperm telomere length, measured as T/S ratio (average ratio of telomere repeats copy number to a single copy gene), was higher in group A than in group B bulls (0.77 ± 0.03 vs 0.43 ± 0.06; P < 0.01). Sperm telomere length was positively correlated with motility, viability and membrane integrity, and it was negatively correlated with sperm anomalies. Furthermore, Percoll gradient selected sperms with higher T/S ratio than unselected sperms (1.19 ± 0.02 vs 0.67 ± 0.03). These results suggest that sperm telomere length can be used as a new marker of bovine semen quality.

Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P =0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P =0.03) and HLs (P= 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P= 0.01) and HLs (P= 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.