Human Telomere Research Articles

Human telomere double G-quadruplex recognition by berberine-bisquinolinium imaging conjugates in vitro and in cells

Molecular tools for double or multimeric G-quadruplexes have recently received high attention due to the possibility to increase detection sensitivity, thermal stabilization and cell imaging opportunities, in oder to determine roles and functions of G-quadruplex aggregation in medical context. In this study, two smart berberine-bisquinolinium conjugates (Ber-360A and Ber-PDS), obtained by linking the berberine fluorophore to established G-quadruplex binders (with bisquinolinium scaffold), have been synthesized and evaluated for their G-quadrulex affinity, as well as to establish mechanisms of aggregation. The conjugates are two highly selective, sensitive and fluorescent sensors able to distinguish human telomere double G-quadruplexes from other type of G-quadruplexes and ds DNA. These ligands are the first example of fluorescent tools that bind to two adjacent G-quadruplex units and optically recognize double structures. Furthermore, microscopy experiments demonstrate that the conjugate Ber-PDS enters the nucleoli and targets G-quadruplex DNA in these organelles, by simultaneously displaying a strong telomerase inhibition and antitumor activity.

ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization.

SummaryTelomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, Origin Recognition Complex-Associated (ORCA/LRWD1), by localizing at the ALT-telomeres, modulates HR activity. ORCA's localization to the ALT-telomeres is facilitated by its interaction to SUMOylated shelterin components. The loss of ORCA in ALT-positive cells elevates the levels of two mediators of HR, RPA and RAD51, and consistent with this, we observe increased ALT-associated promyelocytic leukemia body formation and telomere sister chromatid exchange. ORCA binds to RPA and modulates the association of RPA to telomeres. Finally, the loss of ORCA causes global chromatin decondensation, including at the telomeres. Our results demonstrate that ORCA acts as an inhibitor of HR by modulating RPA binding to ssDNA and inducing chromatin compaction.

Nutrient modulation of DNA repair in lung cancer

Noncommunicable diseases associated with aging and inflammation is rising in recent decades, contributing global burden of disease globally. Among them are cardiovascular diseases, diabetes, and cancer. Our objective is to illustrate the molecular mechanisms behind the chemoprotective effects of major dietary carotenoids. We hypothesize that carotenoids play a role in modulating genome stability. Telomeres are essential for the stability of our genome, and oxidative stress caused by the reactive oxygen species poses a risk for telomere shortening, thereby contributing to the pathogenesis of chronic diseases, including lung cancer. Human telomeres are composed of 10–15 kilobases of TTAGGG repeats. Guanine is the most readily oxidized of the natural bases, and TTAGG repeats are preferred sites for conversion of Guanine to 8‐oxoG, which repaired by base excision repair through an enzyme called OGG1. In the current study, we investigated mRNA and protein expression of OGG1 and retinoic acid receptors (RARs) in human alveolar epithelial cells exposed to cigarette smoke. Cells pre‐treated with various doses of β‐carotene for 24 hours, and the following day exposed to smoke using a smoking chamber. We found out that while β‐carotene increased OGG1 expression at lower doses, it led to a dramatic decrease at higher concentrations suggesting that at higher doses β‐carotene exerted a pro‐oxidant effect. Previously it was reported that the expression of the RARβ, putative tumor suppressor gene, is reduced in lung cancer. In parallel to OGG1 inhibition, we observed decreased levels of RARβ. We are in the process of quantifying 8‐oxoG by HPLC‐MS/MS. We believe that these novel findings will shed light on the mechanism of action of β‐carotene at the molecular level.Support or Funding InformationUSDA‐NIFA Hatch Project

Synthetic Oligodeoxynucleotides in the Regulation of Leukotriene Synthesis in Human Neutrophils

Polymorphonuclear leukocytes (PMNLs, neutrophils) play a central role in the defense against microbial infections. In the immune response to bacterial and fungal infections neutrophils eliminate pathogens through phagocytosis. During phagocytosis neutrophils produce physiologically active compounds called leukotrienes. Neutrophil production of leukoriene B4 is responsible for a second wave of neutrophil recruitment during inflammation. In the activation of neutrophils, not only the bacteria themselves play a role, but also pathogen associated molecular patterns, in particular, bacterial DNA and its fragments. Neutrophil priming with bacterial products makes neutrophils more responsive to activating stimuli. Synthetic CpG‐oligodeoxynucleotides (CpG‐ODNs) mimic microbial DNA and are now widely used to study DNA‐mediated cellular events. In our study we compared the effects of synthetic oligodeoxynucleotides (ODNs) of different structure on leukotriene synthesis in neutrophils during Salmonella bacteria phagocytosis. We treated PMNLs with opsonized S. typhimurium at a ratio of bacteria:PMNLs in the range 20–25:1. Leukotrienes and other 5‐lipoxygenase products were detected after priming neutrophils by 30 min incubation with 1 μM ODN and further stimulation for 15 min with opsonized Salmonella bacteria. The neutrophil exposure to A‐class CpG‐ODN, with phosphodiester inner core, inhibited leukotriene synthesis in neutrophil interaction with bacteria Salmonella typhimurium. Sequences, containing the human telomeric (TTAGGG)n repeats, on the contrary, activated leukotriene synthesis. Effects of A‐class CpG‐ODNs were sensitive to inhibitors of endosomal acidification and probably induced intracellular signaling through binding to toll like receptor TLR9. Synthetic DNA fragments containing stimulating CpG motifs initiate TLR9 signals, which lead to activation of the transcription factor NF‐kB. In our assays NF‐kB inhibitor BAY11‐7082 abolished the effects of A‐class CpG ODNs and increased the effects of telomeric ODNs on leukotriene synthesis. The results of our study revealed that the signal to inhibition of leukotriene synthesis by A‐class CpG‐ODNs and to activation of leukotriene synthesis by telomeric ODNs may be due to interaction of both classes of ODNs with TLR9 on neutrophils.Ethics statement. The authors prepared neutrophils from the blood of healthy volunteers. Blood was collected via venous puncture, as approved by the Ministry of Public Health Service of the Russian Federation. Experimental and the subject consent procedures were approved by the Ethics Committee of the A. N. Belozersky Institute of Physico‐Chemical Biology, Moscow State University. Fully informed consent was obtained, and all investigations were conducted according to the principles laid down in the Declaration of Helsinki.Support or Funding InformationThis study was funded by a grant from the Russian Foundation for Basic Research (17‐04‐01491)

Screening the binding potential of quercetin with parallel, antiparallel and mixed G-quadruplexes of human telomere and cancer protooncogenes using molecular docking approach

The bioinformatics analysis revealed that more than 400,000 DNA sequences within the human genome have the potential of forming G-quadruplex structures. Specifically, G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, transcription and translation of cancer-related genes and hence a therapeutic target. Targeting G4 with small molecules may regulate its expression. Chemical molecules generally shows more cellular toxicity while natural small molecules are more bioavailable and hence shows high biological activity together with low toxicity. In the present study, we have screened the binding potential of quercetin with parallel, anti-parallel and mixed conformations of telomeric G-quadruplexes, cancer protoncogenes and RNA G-quadruplex using molecular docking approach. Our results suggest that the quercetin mainly binds with grooves of all selected G-quadruplxes and its planer aromatic rings stabilizes the structure by π-π stacking. The binding energies were in a range of − 40.24 to − 17.11 kcal/mol, − 35.73 to − 18.09 kcal/mol, − 32.68 to − 22.47 kcal/mol for telomeric parallel, anti-parallel and mixed G-quadruplexes respectively. Further, binding energies of quercetin with selected cancer proto-oncogenes are in a range of − 38.67 to − 12.95 kcal/mol and − 14.8 and − 14.6 kcal/mol for selected RNA G-quadruplex. Hence, this study highlights the comparative differences in binding energies of quercetin even with a group of single conformation of G-quadruplex and helpful to evaluate the binding potential of quercetin to inhibit the activity of telomerases and down-regulate the expression of oncogenes and to be used as a potential anti-cancer agent.

Folding intermediate states of the parallel human telomeric G-quadruplex DNA explored using Well-Tempered Metadynamics

An increasingly comprehension of the folding intermediate states of DNA G-quadruplexes (G4s) is currently an important scientific challenge, especially for the human telomeric (h-tel) G4s-forming sequences, characterized by a highly polymorphic nature. Despite the G-triplex conformation was proposed as one of the possible folding intermediates for the antiparallel and hybrid h-tel G4s, for the parallel h-tel topology with an all-anti guanine orientation, a vertical strand-slippage involving the G-triplets was proposed in previous works through microseconds-long standard molecular dynamics simulations (MDs). Here, in order to get further insights into the vertical strand-slippage and the folding intermediate states of the parallel h-tel G4s, we have carried out a Well-Tempered Metadynamics simulation (WT-MetaD), which allowed us to retrieve an ensemble of six G4s having two/G-tetrad conformations derived by the G-triplets vertical slippage. The insights highlighted in this work are aimed at rationalizing the mechanistic characterisation of the parallel h-tel G4 folding process.

The association between dietary quality indices and serum telomerase activity in patient candidates for CABG.

Diet and dietary habits are major determinants of human telomere length. Telomerase activity is affected mostly by oxidative stress and inflammation. However, the association of telomerase activity with dietary quality indices has not been evaluated before. In the current work, we aimed to test the association of telomerase activity with dietary antioxidant quality score (DAQ), dietary inflammatory index and dietary patterns in patients who were candidate for coronary artery bypass grafting surgery (CABG). In the current cross-sectional study, 454 candidates for the CABG were enrolled from Tehran Heart Center-Coronary Outcome Measurement (THC-COM) cohort. Laboratory measurements included Hb-A1C, serum lipid profile, creatinine, blood urea nitrogen, hematocrit, lipoprotein (LP)-a, telomerase activity, serum vitamin D and C-reactive protein. Dietary status was measured by semiquantitative food frequency questionnaire, and dietary indices were calculated. Dietary patterns were extracted by factor analysis method. High telomerase activity was associated with lower prevalence of myocardial infarction (MI) (P = 0.04), high dietary vitamin E and high total dietary antioxidant quality scores. Telomerase activity in top quartile of neo-traditional dietary pattern was higher than other quartiles (P = 0.021). No significant association between telomerase activity and other dietary patterns was obtained. Higher telomerase activity was also associated with higher serum creatinine and lower LP-(a) concentrations (P < 0.05). To our findings, higher telomerase activity was associated with higher DAQ and lower MI prevalence. It seems that adherence to healthy diet increases serum telomerase activity and reduced telomerase concentration is associated with increased cardio-metabolic risk factors. Moreover, adherence to neo-traditional pattern with higher intake of low-fat dairy products was associated with higher telomerase activity. Level V: A well-designed observational cross-sectional study.

The Potential of Telomeric G-quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils.

Human neutrophils are the first line of defense against bacterial and viral infections. They eliminate pathogens through phagocytosis, which activate the 5-lipoxygenase (5-LOX) pathway resulting in synthesis of leukotrienes. Using HPLC analysis, flow cytometry, and other biochemical methods, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs) able to fold into G-quadruplex structures on the main functions of neutrophils. Designed ODNs contained four human telomere TTAGGG repeats (G4) including those with phosphorothioate oligoguanosines attached to the end(s) of G-quadruplex core. Just modified analogues of G4 was shown to more actively than parent ODN penetrate into cells, improve phagocytosis of Salmonella typhimurium bacteria, affect 5-LOX activation, the cytosol calcium ion level, and the oxidative status of neutrophils. As evident from CD and UV spectroscopy data, the presence of oligoguanosines flanking G4 sequence leads to dramatic changes in G-quadruplex topology. While G4 folds into a single antiparallel structure, two main folded forms have been identified in solutions of modified ODNs: antiparallel and dominant, more stable parallel. Thus, both the secondary structure of ODNs and their ability to penetrate into the cytoplasm of cells are important for the activation of neutrophil cellular effects. Our results offer new clues for understanding the role of G-quadruplex ligands in regulation of integral cellular processes and for creating the antimicrobial agents of a new generation.

Exploring the interaction of G-quadruplex and porphyrin derivative by single protein nanopore sensing interface

Both human telomere and proto-oncogene c-MYC can form G-quadruplex (G4) with various conformations. Porphyrin derivative (TMPyP4) could stabilize G4, and thus is considered as a potential drug for anticancer therapeutics. In this paper, the translocation behaviors of three typical G4s (telomere basket, telomere hybrid-1 and c-MYC Pu22 parallel) and their interaction with TMPyP4 were investigated with a single protein nanopore sensing interface with the same main electrolyte of 0.5 M tetramethylammonium chloride. As observed by the statistics of the dwell time of the current pulses, in the presence of K+, the parallel G4 is more stable than the hybrid-1 G4, while the basket G4 in the presence of Na+ exhibited shortest duration. The dwell time of all of the G4s increased as the result of interaction with TMPyP4, indicating an obvious stabilizing effect. This study demonstrated that the single nanopore sensing interface not only reveal the stability of various G4 conformations at a single-molecule level, but also provide the interaction information of a ligand, which could be useful in the drug design.

Retracted: Molecular insight into the selective binding between human telomere G‐quadruplex and a negatively charged stabilizer

The single-strand human telomere overhang forms intramolecular high-order structures named G-quadruplex (G4) under physiological conditions. Telomere G4 stabilization prevents telomere lengthening by telomerase in cancer cells representing a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) to the human hybrid (3+1) G4s was investigated at the atomic level. We found that APC preferred the end-stacking binding with the telomere hybrid type II (hybrid-II) G4 as compared to the groove binding with the hybrid type I (hybrid-I) G4 remarkable stabilizing effect and more favourable binding free energies. Analysis of non-covalent interaction and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s. These findings provide evidence for the first time to shed light on the designs of selective telomere G4 stabilizers.

Current trends in human dental telomere length measurements in forensic age estimation - a narrative review

Tooth, due to the anatomical framework of hard minerals, is a reliable source in forensic identification, sex determination, and age estimation. Although Morphological, radiological, and histological methods are effective methods, the advancements in molecular methods have shifted the focus of research towards changes occurring in DNA to age and sex. Molecular methods are useful when other methods fail to estimate the age. Telomere length attrition and DNA methylation are the two extensively studied areas in dental forensic age estimation. This review attempts to narrate the current trends in human dental telomere length measurement & its applications.

CRISPR-Cas12a trans-cleaves DNA G-quadruplexes.

We for the first time report that the activated CRISPR-Cas12a system trans-cleaves DNA G-quadruplexes (G4). The cleavage activity on human telomere G4 and TBA G4 was investigated and verified by FRET, CD, gel electrophoresis and NMR. We believe that this finding will pave a new avenue for advancing the applications of CRISPR-Cas12a and G4 in biosensing and biochemistry.

Dimers formed with the mixed-type G-quadruplex binder pyridostatin specifically recognize human telomere G-quadruplex dimers.

By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.

Mutational profiling of POT1 gene and its interaction with TPP1 in cancer- A computational approach

Abstract Telomeres are specialized structures at the end of eukaryotic chromosomes that maintain genomic stability by preventing chromosomal rearrangements and thereby enabling semi-conservative replication of telomeric DNA. The length of telomeric DNA is retained by telomerase that balances between the processes that lengthen and shorten the telomeres. In human chromosomes, six telomere-associated proteins namely- TRF1, TRF2, POT1, RAP1, TIN2, and TPP1 form the shelterin complex, that is essential for maintenance of telomeric integrity. The human POT1 and TPP1 play a major role in protecting the ssDNA overhangs, formed due to the end replication problem. These proteins along with other repair complexes protect the telomere overhangs from cellular repair complexes. However, shelterin functionality can become compromised due to mutations in any of the six genes and can lead to unwarranted repair of the human telomeres. In cancer and transformed cells, telomerase activation replenishes the telomeres while also, recruiting repair proteins at the telomeres. With an aim to evaluate the functional consequence of non-synonymous single nucleotide polymorphisms (nsSNPs) in POT1 gene variants, and resulting changes that affect its interactions with TPP1, this research was carried out using computational tools. The overall outcomes revealed 16 POT1 gene mutations that were likely to impact the protein function. Of these 9 mutations, viz., P357S, H437P, V439G, P475L, G534C, P537S, F566C, M587T, and C591W showed that the altered POT1 function impacted its interaction with TPP1 protein. The binding affinity of POT1 with ssDNA overhangs was also changed. A wet-lab follow-up study using site-directed mutagenesis and yeast hybridization techniques can help exploit underlying mechanisms affecting stable association of these two shelterin components.

Metalloenzyme-mimic innate G-quadruplex DNAzymes using directly coordinated metal ions as active centers.

G-quadruplex DNAs (G4s) have been reported to exhibit the DNAzyme activities by binding with some metal complexes and functional organic ligands. However, there is a challenge to develop metalloenzyme-mimic G4-based innate DNAzymes using the complexed metal ions directly serving as the active centers. This will diversify DNAzymes for developing novel devices since G4 structures are more polymorphic than the other DNA foldings. In this work, we found that the lanthanide trivalent cerium ion of Ce3+ can bind to the human telomere G4 (htG4) according to a 1 : 2 binding mode favorable for creating metalloenzymes-mimic G4 DNAzymes. This Ce3+-G4 entity exhibits a peroxidase activity towards the oxidation of the substrate of 3,3,5,5-tetramethylbenzidine (TMB) by hydrogen peroxide. The 5' G4 tetrads with the orderly arranged carbonyl oxygen atoms are believed to be the coordination sites for Ce3+ and favor the conversion between Ce3+ and Ce4+. Our work provides an alternative feasibility in developing the G4-based innate DNAzymes for variant applications.

HKR3 regulates cell cycle through the inhibition of hTERT in hepatocellular carcinoma cell lines.

Hepatocellular carcinoma is a malignant disease with improved hepatic regeneration and survival, and is activated by human telomere transferase (hTERT). hTERT is expressed during early fetal development and switched off in most adult tissues, but it becomes reactivated in HCC. The exact mechanism regulating these expression changes remains unknown during HCC progress. We evaluated the relationship between hTERT expression and human kruppel-related 3 (HKR3) and cell cycle-related factors in HCC cell lines. Following transfection for hTERT knockdown and HKR3 overexpression, proteomic and transcriptomic analyses related to hTERT were performed using liquid chromatography/mass spectrometry (LC/MS) and RNA sequencing (RNAseq) in HCC cell lines. The expression levels of hTERT, HKR3, and cell cycle-related factors were measured using western blotting, and tumor growth were evaluated via cell proliferation and cell cycle assays. Transcriptomic and proteomic analyses showed that HKR3, hTERT and cyclin-dependent kinase inhibitor 2A (CDKN2A) were correlated. Up-regulation of HKR3 expression decreased hTERT and cyclin activation and suppressed the G1/S phase of the cell cycle through CDKN2A activation. Our results suggest that HKR3 induced regulation of cell cycle through hTERT inhibition and CDKN2A activation. Our results will facilitate further exploration of the pathways regulating human telomerase activity in HCC cell lines.

Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.

Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

Regulation of Telomere Length and Atherosclerosis by Protection of Telomeres 1 Protein.

The aim of this study was to investigate the manifestation and significance of changes in both telomere length and the expression of human telomere protective protein (hPOT1) in the peripheral blood leukocytes of patients with atherosclerosis (AS). One hundred subjects-excluding those with acute or chronic inflammation, cancer, and autoimmune diseases-were enrolled in this study and divided into two groups: the atherosclerosis group (AS group) and control group. We extracted peripheral blood leukocyte DNA along with its peripheral proteins. After purity testing, a digoxigeninlabeled telomere probe was used for Southern blotting; the length of the telomeres was obtained by image scanning and software analysis. After extracting the peripheral proteins, hPOT1 expression was detected by western blotting and scanned with an image analysis software system. We found that the telomere lengths in the peripheral blood leukocytes of AS and control groups were 7.45 ± 1.15 kb versus 8.11 ± 0.69 kb, respectively, and that the difference between them was statistically significant (p < 0.005). The expression level of hPOT1 protein in the peripheral blood leukocytes of the AS group was significantly higher than that of the control group (t = 3.77, p < 0.01). As can be determined from these results, telomere length in the peripheral blood leukocytes of AS patients was significantly shorter compared with that of the control group. The regulation of telomere length by hPOT1 by negative regulation may be one of the influencing factors in AS. Therefore, it is suggested that change in telomere length may play a role in the occurrence and development of AS.

Real-time Monitoring Excitation Dynamics of Human Telomeric Guanine Quadruplexes: Effect of Folding Topology, Metal Cation, and Confinement by Nanocavity Water Pool.

Guanine(G)-rich human telomeric (HT) DNA repeats, crucial to maintenance of genome stability, readily form G-quadruplexes (GQs) with various folding topologies. Research on excitation dynamics of HT-GQs is, however, scarce. Herein, we report a femtosecond time-resolved fluorescence coupled with transient absorption investigation on HT-GQ with the basket-type structure in Na+ solution. The result unveils an unusual multichannel nonradiative mechanism dominated by states with varying character of charge transfer lasting ten and hundreds of picoseconds, accounting altogether for an overwhelming ∼85% of the overall deactivation involving proton transfer. Our comparative study shows that encapsulating the GQ in nanocavity water pool or changing it into hydrid-type topologies with the presence of K+ ions alter differently energies and lifetimes of these states, yet without affecting the nature of the electronic excitation involved. The finding of this work underscores a leading role of structural rigidity in regulating the interplay with the microenvironment of photoexcited monomolecularly folded HT-GQs.

Hole Migration in Telomere-Based Oligonucleotide Anions and G-Quadruplexes.

Vacuum ultraviolet photoionization of a gas‐phase oligonucleotide anion leads to the formation of a valence hole. This hole migrates towards an energetically favorable site where it can weaken bonds and ultimately lead to bond cleavage. We have studied Vacuum UV photoionization of deprotonated oligonucleotides containing the human telomere sequence dTTAGGG and G‐quadruplex structures consisting of four dTGGGGT single strands, stabilized by NH4 + counter ions. The oligonucleotide and G‐quadruplex anions were confined in a radiofrequency ion trap, interfaced with a synchrotron beamline and the photofragmentation was studied using time‐of‐flight mass spectrometry. Oligonucleotide 12‐mers containing the 5'‐TTAGGG sequence were found to predominantly break in the GGG region, whereas no selective bond cleavage region was observed for the reversed 5'‐GGGATT sequence. For G‐quadruplex structures, fragmentation was quenched and mostly non‐dissociative single and double electron removal was observed.