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Biological Chemistry Mar 2019The shelterin complex protects telomeric DNA and plays critical roles in maintaining chromosome stability. The structures and functions of the shelterin complex have... (Review)
Review
The shelterin complex protects telomeric DNA and plays critical roles in maintaining chromosome stability. The structures and functions of the shelterin complex have been extensively explored in the past decades. This review summarizes the current progress on structural studies of shelterin complexes from different species. It focuses on the structural features and assembly of common structural domains, highlighting the evolutionary plasticity and conserved roles of shelterin proteins in telomere homeostasis and protection.
Topics: DNA; Humans; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 30352022
DOI: 10.1515/hsz-2018-0368 -
Molecular Cell Nov 2017In this issue of Molecular Cell, Kim et al. (2017) have studied the structure and organization of the shelterin protein complex protecting telomeres in... (Review)
Review
In this issue of Molecular Cell, Kim et al. (2017) have studied the structure and organization of the shelterin protein complex protecting telomeres in Schizosaccharomyces pombe and humans and discovered an allosteric structural transition that drives the formation of the shelterin complex and participates in telomere length regulation.
Topics: Humans; Schizosaccharomyces; Shelterin Complex; Telomere; Telomere Homeostasis; Telomere-Binding Proteins
PubMed: 29149592
DOI: 10.1016/j.molcel.2017.11.005 -
Genes & Development Dec 2021The mammalian telomeric shelterin complex-comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-blocks the DNA damage response at chromosome ends and interacts with...
The mammalian telomeric shelterin complex-comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins.
Topics: Animals; Mammals; Shelterin Complex; Telomere; Telomere-Binding Proteins; Telomeric Repeat Binding Protein 2; Tripeptidyl-Peptidase 1
PubMed: 34764137
DOI: 10.1101/gad.348835.121 -
Genes & Development Sep 2022Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking... (Review)
Review
Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking telomerase due to the end replication problem. In addition, recent work uncovered that the bulk of telomeric DNA poses severe hurdles for the semiconservative DNA replication machinery, requiring the assistance of an increasing number of specialized factors that prevent accidental telomere loss or damage events. In this issue of , Yang and colleagues (pp. 956-969) discover that TFIIH, a basic component of the PolII transcription initiation and nucleotide excision repair machinery, facilitates telomere replication. TFIIH is recruited to telomeres by the shelterin component TRF1, taking on at telomeres a moonlighting function.
Topics: Telomeric Repeat Binding Protein 1; Telomere; Telomere Shortening; Telomere-Binding Proteins; Telomerase; Shelterin Complex
PubMed: 36347559
DOI: 10.1101/gad.350140.122 -
International Journal of Molecular... Jun 2019The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent... (Review)
Review
The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies.
Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; Humans; Protein Binding; Shelterin Complex; Telomerase; Telomere-Binding Proteins
PubMed: 31261825
DOI: 10.3390/ijms20133186 -
Pflugers Archiv : European Journal of... Nov 2022Ageing causes a gradual deterioration of bodily functions and telomere degradation. Excessive telomere shortening leads to cellular senescence and decreases tissue...
Ageing causes a gradual deterioration of bodily functions and telomere degradation. Excessive telomere shortening leads to cellular senescence and decreases tissue vitality. Six proteins, called shelterin, protect telomere integrity and control telomere length through telomerase-dependent mechanisms. Exercise training appears to maintain telomeres in certain somatic cells, although the underlying molecular mechanisms are incompletely understood. Here, we examined the influence of a single bout of vigorous exercise training on leukocyte telomerase reverse transcriptase (TERT) and shelterin gene expression, and the abundance of three microRNAs (miRNAs) implicated in biological ageing (miRNA-143, -223 and -486-5p) in an elite athlete and large animal model, Thoroughbred horses. Gene and miRNA expression were analysed using primer-based and TaqMan Assay qPCR. Leukocyte TRF1, TRF2 and POT1 expression were all significantly increased whilst miR-223 and miR-486-5p were decreased immediately after vigorous exercise (all p < 0.05), and tended to return to baseline levels 24 h after training. Relative to the young horses (~ 3.9 years old), middle-aged horses (~ 14.8 years old) exhibited reduced leukocyte TERT gene expression, and increased POT1 and miR-223 abundance (all p < 0.05). These data demonstrate that genes transcribing key components of the shelterin-telomere complex are influenced by ageing and dynamically regulated by a single bout of vigorous exercise in a large, athletic mammal - Thoroughbred horses. Our findings also implicate TERT and shelterin gene transcripts as potential targets of miR-223 and miR-486-5p, which are modulated by exercise and may have a role in the telomere maintenance and genomic stability associated with long-term aerobic training.
Topics: Aging; Animals; Horses; Mammals; MicroRNAs; Shelterin Complex; Telomerase; Telomere
PubMed: 36085194
DOI: 10.1007/s00424-022-02745-0 -
Proceedings of the National Academy of... Aug 2022Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and...
Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been generated of the individual structured domains within shelterin, the architecture and stoichiometry of the full complex are currently unknown. Here, we report the purification of shelterin subcomplexes and reconstitution of the entire complex using full-length, recombinant subunits. By combining negative-stain electron microscopy (EM), cross-linking mass spectrometry (XLMS), AlphaFold modeling, mass photometry, and native mass spectrometry (MS), we obtain stoichiometries as well as domain-scale architectures of shelterin subcomplexes and determine that they feature extensive conformational heterogeneity. For POT1/TPP1 and POT1/TPP1/TIN2, we observe high variability in the positioning of the POT1 DNA-binding domain, the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold, and the TIN2 TRFH domain with respect to the C-terminal domains of POT1. Truncation of unstructured linker regions in TIN2, TPP1, and POT1 did not reduce the conformational variability of the heterotrimer. Shelterin and TRF1-containing subcomplexes form fully dimeric stoichiometries, even in the absence of DNA substrates. Shelterin and its subcomplexes showed extensive conformational variability, regardless of the presence of DNA substrates. We conclude that shelterin adopts a multitude of conformations and argue that its unusual architectural variability is beneficial for its many functions at telomeres.
Topics: Humans; Mass Spectrometry; Microscopy, Electron; Protein Domains; Shelterin Complex
PubMed: 35881804
DOI: 10.1073/pnas.2201662119 -
Pharmacology & Therapeutics Apr 2021The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter... (Review)
Review
The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.
Topics: DNA; Humans; Occupational Health; Shelterin Complex; Telomere; Telomere Homeostasis; Telomere-Binding Proteins; Toxicology
PubMed: 33176178
DOI: 10.1016/j.pharmthera.2020.107742 -
Nucleus (Austin, Tex.) 2011The processes regulating telomere function have major impacts on fundamental issues in human cancer biology. First, active telomere maintenance is almost always required... (Review)
Review
The processes regulating telomere function have major impacts on fundamental issues in human cancer biology. First, active telomere maintenance is almost always required for full oncogenic transformation of human cells, through cellular immortalization by endowment of an infinite replicative potential. Second, the attrition that telomeres undergo upon replication is responsible for the finite replicative life span of cells in culture, a process called senescence, which is of paramount importance for tumor suppression in vivo. The process of telomere-based senescence is intimately coupled to the induction of a DNA damage response emanating from telomeres, which can be elicited by both the ATM and ATR dependent pathways. At telomeres, the shelterin complex is constituted by a group of six proteins which assembles quantitatively along the telomere tract, and imparts both telomere maintenance and telomere protection. Shelterin is known to regulate the action of telomerase, and to prevent inappropriate DNA damage responses at chromosome ends, mostly through inhibition of ATM and ATR. The roles of shelterin have increasingly been associated with transient interactions with downstream factors that are not associated quantitatively or stably with telomeres. Here, some of the important known interactions between shelterin and these associated factors and their interplay to mediate telomere functions are reviewed.
Topics: Animals; Base Sequence; Chromosomes, Human; Humans; Neoplasms; Nucleotide Motifs; Repetitive Sequences, Nucleic Acid; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 21738835
DOI: 10.4161/nucl.2.2.15135 -
Aging Cell May 2023Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in...
Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation. Indeed, the subtelomeres containing these derepressed genes are enriched in factors of polycomb repression (EZH2 and H3K27me3), insulation (CTCF and MAZ), and cohesion (RAD21 and SMC3) while being associated with the open A-type chromatin compartment. These findings unveil that the subtelomere transcriptome associated with senescence is determined in a chromosome-end-specific manner according to the type of higher-order chromatin structure.
Topics: Telomere; Chromatin; Heterochromatin; Gene Expression Regulation; Shelterin Complex; Cellular Senescence
PubMed: 36924026
DOI: 10.1111/acel.13804