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Cellular and Molecular Life Sciences :... Jan 2020Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric... (Review)
Review
Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.
Topics: Aminopeptidases; Animals; Chromosomes; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Models, Molecular; Protein Conformation; Serine Proteases; Shelterin Complex; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 31728577
DOI: 10.1007/s00018-019-03369-x -
EMBO Molecular Medicine Jan 2023The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly...
The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood-brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.
Topics: Animals; Humans; Mice; Apoptosis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; MicroRNAs; Telomere; Triple Negative Breast Neoplasms
PubMed: 36426578
DOI: 10.15252/emmm.202216033 -
Current Opinion in Structural Biology Dec 2022Eukaryotic DNA is packaged into nucleosomes, which further condenses into chromosomes. The telomeres, which form the protective end-capping of chromosomes, play a... (Review)
Review
Eukaryotic DNA is packaged into nucleosomes, which further condenses into chromosomes. The telomeres, which form the protective end-capping of chromosomes, play a pivotal role in ageing and cancer. Recently, significant advances have been made in understanding the nucleosomal and telomeric chromatin structure at the molecular level. In addition, recent studies shed light on the nucleosomal organisation at telomeres revealing its ultrastructural organisation, the atomic structure at the nucleosome level, its dynamic properties, and higher-order packaging of telomeric chromatin. Considerable advances have furthermore been made in understanding the structure, function and organisation of shelterin, telomerase and CST complexes. Here we discuss these recent advances in the organisation of telomeric nucleosomes and chromatin and highlight progress in the structural understanding of shelterin, telomerase and CST complexes.
Topics: Telomere; Nucleosomes; Chromatin; Telomerase; DNA
PubMed: 36335846
DOI: 10.1016/j.sbi.2022.102492 -
Nature Reviews. Molecular Cell Biology Apr 2021The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires... (Review)
Review
The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the 'telomere replisome') and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1-STN1-TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.
Topics: Animals; Chromatin; Chromosomes; DNA; Humans; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 33564154
DOI: 10.1038/s41580-021-00328-y -
Computational and Structural... 2020Telomeres are DNA repeats at the ends of linear chromosomes and are replicated by telomerase, a ribonucleoprotein reverse transcriptase. Telomere length regulation and... (Review)
Review
Telomeres are DNA repeats at the ends of linear chromosomes and are replicated by telomerase, a ribonucleoprotein reverse transcriptase. Telomere length regulation and chromosome end capping are essential for genome stability and are mediated primarily by the shelterin and CST complexes. POT1-TPP1, a subunit of shelterin, binds the telomeric overhang, suppresses ATR-dependent DNA damage response, and recruits telomerase to telomeres for DNA replication. POT1 localization to telomeres and chromosome end protection requires its interaction with TPP1. Therefore, the POT1-TPP1 complex is critical to telomere maintenance and full telomerase processivity. The aim of this mini-review is to summarize recent POT1-TPP1 structural studies and discuss how the complex contributes to telomere length regulation. In addition, we review how disruption of POT1-TPP1 function leads to human disease.
PubMed: 32774788
DOI: 10.1016/j.csbj.2020.06.040 -
Chromosoma Mar 2016Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA... (Review)
Review
Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA repeats associated with telomerase have been found in some plant and animal species. Telomerase was likely lost from Diptera before the divergence of Diptera and Siphonaptera, some 260 million years ago. Even so, Diptera is one of the most successful animal orders, making up 11% of known animal species. In addition, many species of Coleoptera and Hemiptera seem to lack canonical telomeric repeats at their chromosome ends. These and other insects that appear to lack canonical terminal repeat sequences account for another 10-15% of animal species. Conversely, the silk moth Bombyx mori maintains canonical telomeric sequences at its chromosome ends but seems to lack a functional telomerase. We speculate that a telomere-specific capping complex that recognizes the telomeric repeats and protects chromosome ends is the determining factor in maintaining canonical telomeric sequences and that telomerase is an early and efficacious mechanism for satisfying the needs of capping complex. There are alternate mechanisms for maintaining chromosome ends that do not depend on telomerase, such as recombination found in some human cancer cells and yeast mutants. These mechanisms may maintain the canonical telomeric repeats or allow the terminal sequence to evolve when specificity of the capping complex for terminal repeat sequences is weak.
Topics: Animals; Evolution, Molecular; Gene Deletion; Homologous Recombination; Insecta; Telomerase; Telomere; Terminal Repeat Sequences
PubMed: 26162505
DOI: 10.1007/s00412-015-0528-7 -
Parasitology Research Apr 2024Giardia duodenalis, the protozoan responsible for giardiasis, is a significant contributor to millions of diarrheal diseases worldwide. Despite the availability of... (Review)
Review
Giardia duodenalis, the protozoan responsible for giardiasis, is a significant contributor to millions of diarrheal diseases worldwide. Despite the availability of treatments for this parasitic infection, therapeutic failures are alarmingly frequent. Thus, there is a clear need to identify new therapeutic targets. Giardia telomeres were previously identified, but our understanding of these structures and the critical role played by Giardia telomerase in maintaining genomic stability and its influence on cellular processes remains limited. In this regard, it is known that all Giardia chromosomes are capped by small telomeres, organized and protected by specific proteins that regulate their functions. To counteract natural telomere shortening and maintain high proliferation, Giardia exhibits constant telomerase activity and employs additional mechanisms, such as the formation of G-quadruplex structures and the involvement of transposable elements linked to telomeric repeats. Thus, this study aims to address the existing knowledge gap by compiling the available information (until 2023) about Giardia telomeres and telomerase, focusing on highlighting the distinctive features within this parasite. Furthermore, the potential feasibility of targeting Giardia telomeres and/or telomerase as an innovative therapeutic strategy is discussed.
Topics: Humans; Telomerase; Giardiasis; Giardia; Telomere; Giardia lamblia
PubMed: 38584235
DOI: 10.1007/s00436-024-08200-6 -
Genes To Cells : Devoted To Molecular &... Apr 2021In eukaryotes, specific DNA-protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex....
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.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Cell Nucleus; Chromosomal Proteins, Non-Histone; DNA Breaks, Double-Stranded; Drosophila Proteins; Drosophila melanogaster; Endodeoxyribonucleases; Protein Binding; Protein Transport; Telomere
PubMed: 33556205
DOI: 10.1111/gtc.12836 -
Frontiers in Bioscience (Landmark... Jun 2012The nucleoprotein complexes that cap the very ends of the eukaryotic chromosomes, named telomeres, are indispensable for cell viability. Telomeric DNA shortens in each... (Review)
Review
The nucleoprotein complexes that cap the very ends of the eukaryotic chromosomes, named telomeres, are indispensable for cell viability. Telomeric DNA shortens in each cell division until it cannot exert end-protective functions in human somatic cells. Additionally, several proteins have been described to play a key role in telomere homeostasis preventing chromosome extremities to be recognized as double-stranded breaks (DSBs). When telomeres become dysfunctional, either through excessive shortening or due to defects in the proteins that form its structure, they trigger p53/pRb pathways what limits proliferative lifespan. Impairment of telomere function together with a compromised senescence/apoptosis response leads to chromosome instability. Fusions between dysfunctional telomeres or even between dysfunctional telomeres and DSBs can initiate breakage-fusion-bridge (BFB) cycles. Initially, telomere fusions were proposed to cause only structural abnormalities. Nevertheless, changes in chromosome number have also emerged as a possible consequence of alterations in end capping. Here we review the main aspects of telomeres and telomere-based chromosome instability, highlighting why they have been proposed as a driving force for tumourigenesis.
Topics: Animals; Cell Proliferation; Cellular Senescence; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Genomic Instability; Humans; Mice; Models, Genetic; Neoplasms; Shelterin Complex; Telomerase; Telomere; Telomere Homeostasis; Telomere Shortening; Telomere-Binding Proteins
PubMed: 22652771
DOI: 10.2741/4044 -
Trends in Biochemical Sciences Jun 2022Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA... (Review)
Review
Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA replication. Incomplete telomere replication accelerates telomere shortening and limits replicative lifespan. Therefore, continued proliferation under conditions of replication stress requires a means of telomere repair, particularly in the absence of telomerase. It was recently revealed that replication stress triggers break-induced replication (BIR) and mitotic DNA synthesis (MiDAS) at mammalian telomeres; however, these mechanisms are error prone and primarily utilized in tumorigenic contexts. In this review article, we discuss the consequences of replication stress at telomeres and how use of available repair pathways contributes to genomic instability. Current research suggests that fragile telomeres are ultimately tumor-suppressive and thus may be better left unrepaired.
Topics: Animals; DNA Repair; DNA Replication; Genomic Instability; Mammals; Telomerase; Telomere; Telomere Homeostasis
PubMed: 35440402
DOI: 10.1016/j.tibs.2022.03.013