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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 -
Ageing Research Reviews Jan 2022Short telomeres confer risk of degenerative diseases. Chronic psychological stress can lead to disease through many pathways, and research from in vitro studies to human... (Review)
Review
Short telomeres confer risk of degenerative diseases. Chronic psychological stress can lead to disease through many pathways, and research from in vitro studies to human longitudinal studies has pointed to stress-induced telomere damage as an important pathway. However, there has not been a comprehensive model to describe how changes in stress physiology and neuroendocrine pathways can lead to changes in telomere biology. Critically short telomeres or the collapse of the telomere structure caused by displacement of telomere binding protein complex shelterin elicit a DNA damage response and lead to senescence or apoptosis. In this narrative review, we summarize the key roles glucocorticoids, reactive oxygen species (ROS) and mitochondria, and inflammation play in mediating the relationship between psychological stress and telomere maintenance. We emphasis that these mediators are interconnected and reinforce each other in positive feedback loops. Telomere length has not been studied across the lifespan yet, but the initial setting point at birth appears to be the most influential point, as it sets the lifetime trajectory, and is influenced by stress. We describe two types of intergenerational stress effects on telomeres - prenatal stress effects on telomeres during fetal development, and 'telotype transmission" -the directly inherited transmission of short telomeres from parental germline. It is clear that the initial simplistic view of telomere length as a mitotic clock has evolved into a far more complex picture of both transgenerational telomere influences, and of interconnected molecular and cellular pathways and networks, as hallmarks of aging where telomere maintenance is a key player interacting with mitochondria. Further mechanistic investigations testing this comprehensive model of stress mediators shaping telomere biology and the telomere-mitochondrial nexus will lead to better understanding from cell to human lifespan aging, and could lead to anti-aging interventions.
Topics: Aging; Cellular Senescence; Female; Humans; Mitochondria; Pregnancy; Reactive Oxygen Species; Telomerase; Telomere; Telomere Shortening
PubMed: 34736994
DOI: 10.1016/j.arr.2021.101507 -
Journal of Cutaneous Pathology Jul 2020Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations... (Comparative Study)
Comparative Study Review
Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations are responsible for the majority of hereditary melanoma, but many other susceptibility genes have been discovered in recent years, including CDK4, TERT, ACD, TERF2IP, POT1, MITF, MC1R, and BAP1. Additionally, melanoma risk is increased in mixed cancer syndromes caused by mutations in PTEN, BRCA2, BRCA1, RB1, and TP53. While early onset, multiple tumors, and family cancer history remain the most valuable clinical clues for hereditary melanoma, characteristic epithelioid cytology of melanocytic tumors may suggest an underlying BAP1 mutation. Herein, we review the clinical and histopathologic characteristics of melanocytic tumors associated with these germline mutations and discuss the role of genetic counseling.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; Genes, p16; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Melanoma; Microphthalmia-Associated Transcription Factor; Middle Aged; Nevus, Pigmented; Phenotype; Receptor, Melanocortin, Type 1; Shelterin Complex; Telomerase; Telomere-Binding Proteins; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Young Adult
PubMed: 32249949
DOI: 10.1111/cup.13689 -
The New England Journal of Medicine Jun 2023Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is...
BACKGROUND
Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.
METHODS
We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene and noncarrier relatives.
RESULTS
A total of 17 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic and hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, mutation carriers maintained telomere length over the course of 2 years.
CONCLUSIONS
mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).
Topics: Humans; Aging; Clonal Hematopoiesis; Heterozygote; Loss of Function Mutation; Mutation; Neoplasms; Shelterin Complex; Syndrome; Telomere; Telomere Homeostasis; Telomere-Binding Proteins
PubMed: 37140166
DOI: 10.1056/NEJMoa2300503 -
Science (New York, N.Y.) Mar 2022Telomerase maintains genome stability by extending the 3' telomeric repeats at eukaryotic chromosome ends, thereby counterbalancing progressive loss caused by incomplete...
Telomerase maintains genome stability by extending the 3' telomeric repeats at eukaryotic chromosome ends, thereby counterbalancing progressive loss caused by incomplete genome replication. In mammals, telomerase recruitment to telomeres is mediated by TPP1, which assembles as a heterodimer with POT1. We report structures of DNA-bound telomerase in complex with TPP1 and with TPP1-POT1 at 3.2- and 3.9-angstrom resolution, respectively. Our structures define interactions between telomerase and TPP1-POT1 that are crucial for telomerase recruitment to telomeres. The presence of TPP1-POT1 stabilizes the DNA, revealing an unexpected path by which DNA exits the telomerase active site and a DNA anchor site on telomerase that is important for telomerase processivity. Our findings rationalize extensive prior genetic and biochemical findings and provide a framework for future mechanistic work on telomerase regulation.
Topics: Amino Acid Motifs; Catalytic Domain; Cryoelectron Microscopy; DNA; Humans; Models, Molecular; Protein Binding; Protein Conformation; Protein Domains; Protein Interaction Domains and Motifs; Shelterin Complex; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 35201900
DOI: 10.1126/science.abn6840 -
Cell Metabolism Nov 2020Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in...
Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.
Topics: Aging; Aminopeptidases; Animals; Cell Line; Cellular Senescence; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; F-Box-WD Repeat-Containing Protein 7; Humans; Mice; Oxidative Stress; Serine Proteases; Shelterin Complex; Stem Cells; Telomere; Telomere Shortening; Telomere-Binding Proteins
PubMed: 33086033
DOI: 10.1016/j.cmet.2020.10.004 -
Nature Apr 2022Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a...
Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase, and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.
Topics: Binding Sites; Cryoelectron Microscopy; Humans; Protein Binding; Shelterin Complex; Tartrate-Resistant Acid Phosphatase; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 35418675
DOI: 10.1038/s41586-022-04582-8 -
Science (New York, N.Y.) Feb 2017Telomeres are found at the end of chromosomes and are important for chromosome stability. Here we describe a specific telomere-associated protein: TZAP (telomeric zinc...
Telomeres are found at the end of chromosomes and are important for chromosome stability. Here we describe a specific telomere-associated protein: TZAP (telomeric zinc finger-associated protein). TZAP binds preferentially to long telomeres that have a low concentration of shelterin complex, competing with the telomeric-repeat binding factors TRF1 and TRF2. When localized at telomeres, TZAP triggers a process known as telomere trimming, which results in the rapid deletion of telomeric repeats. On the basis of these results, we propose a model for telomere length regulation in mammalian cells: The reduced concentration of the shelterin complex at long telomeres results in TZAP binding and initiation of telomere trimming. Binding of TZAP to long telomeres represents the switch that triggers telomere trimming, setting the upper limit of telomere length.
Topics: Cell Line, Tumor; DNA-Binding Proteins; Gene Knockout Techniques; Humans; Protein Binding; Tandem Repeat Sequences; Telomere; Telomere Homeostasis; Telomeric Repeat Binding Protein 1; Telomeric Repeat Binding Protein 2; Transcription Factors; Zinc Fingers
PubMed: 28082411
DOI: 10.1126/science.aah6752 -
The Journal of Clinical Investigation May 2016Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A... (Review)
Review
Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Chromosomes, Human; DNA Damage; Dyskeratosis Congenita; Hematopoiesis; Hemoglobinuria, Paroxysmal; Humans; Mutation; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 27135879
DOI: 10.1172/JCI84547 -
Life Science Alliance Dec 2021Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces....
Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate than feces from mice without endometriosis. Treatment with n-butyrate reduced growth of both mouse endometriotic lesions and human endometriotic lesions in a pre-clinical mouse model. Mechanistic studies revealed that n-butyrate inhibited human endometriotic cell survival and lesion growth through G-protein-coupled receptors, histone deacetylases, and a GTPase activating protein, RAP1GAP. Our findings will enable future studies aimed at developing diagnostic tests, gut bacteria metabolites and treatment strategies, dietary supplements, n-butyrate analogs, or probiotics for endometriosis.
Topics: Animals; Bacteria; Butyrates; Cell Line, Transformed; Cell Proliferation; Cell Survival; Disease Models, Animal; Endometriosis; Epithelial Cells; Feces; Female; Gastrointestinal Microbiome; Heterografts; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Protective Agents; Shelterin Complex; Signal Transduction; Stromal Cells; Telomere-Binding Proteins; Transfection
PubMed: 34593556
DOI: 10.26508/lsa.202101224