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Genes & Development Sep 2005Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and... (Review)
Review
Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.
Topics: Antigens, Surface; Binding Sites; Cell Adhesion Molecules; Chromosomal Instability; DNA Damage; Humans; Membrane Glycoproteins; Models, Biological; Multiprotein Complexes; Peptide Hydrolases; Protein Binding; Protein Structure, Tertiary; Protein Subunits; Proteins; Shelterin Complex; Tandem Repeat Sequences; Telomere; Telomere-Binding Proteins; Telomeric Repeat Binding Protein 1; Telomeric Repeat Binding Protein 2; rap1 GTP-Binding Proteins
PubMed: 16166375
DOI: 10.1101/gad.1346005 -
Current Opinion in Genetics &... Feb 2020Telomeres are G-rich repetitive sequences that are difficult to replicate, resulting in increased replication stress that can threaten genome stability. Shelterin... (Review)
Review
Telomeres are G-rich repetitive sequences that are difficult to replicate, resulting in increased replication stress that can threaten genome stability. Shelterin protects telomeres from engaging in aberrant DNA repair and dictates the choice of DNA repair pathway at dysfunctional telomeres. Recently, shelterin has been shown to participate in telomere replication. Here we review the most recent discoveries documenting the mechanisms by which shelterin represses DNA repair pathways at telomeres while assisting its replication. The interplay between shelterin and the replisome complex highlights a novel connection between telomere maintenance and repair.
Topics: DNA Damage; DNA Repair; DNA Replication; Genomic Instability; Humans; Neoplasms; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 32171974
DOI: 10.1016/j.gde.2020.02.016 -
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 -
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 -
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 -
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 -
Asian Pacific Journal of Cancer... 2015The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It... (Review)
Review
The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It comprises six proteins, namely TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. All of these assemble together to form a complex with double strand and single strand DNA repeats at the telomere. Such an association contributes to telomere stability and its protection from undesirable DNA damage control-specific responses. However, any alteration in the structure and function of any of these proteins may lead to undesirable DNA damage responses and thus cellular senescence and death. In our review, we throw light on how mutations in the proteins belonging to the shelterin complex may lead to various malfunctions and ultimately have a role in tumorigenesis and cancer progression.
Topics: Animals; DNA Damage; Humans; Neoplasms; Shelterin Complex; Telomere; Telomere-Binding Proteins; Telomeric Repeat Binding Protein 2
PubMed: 25921101
DOI: 10.7314/apjcp.2015.16.8.3085 -
International Journal of Molecular... Nov 2023Telomeres are nucleoprotein complexes that cap the ends of eukaryotic linear chromosomes. Telomeric DNA is bound by shelterin protein complex to prevent telomeric... (Review)
Review
Telomeres are nucleoprotein complexes that cap the ends of eukaryotic linear chromosomes. Telomeric DNA is bound by shelterin protein complex to prevent telomeric chromosome ends from being recognized as damaged sites for abnormal repair. To overcome the end replication problem, cancer cells mostly preserve their telomeres by reactivating telomerase, but a minority (10-15%) of cancer cells use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). Recent studies have found that shelterin components play an important role in the ALT mechanism. The binding of TRF1, TRF2, and RAP1 to telomeres attenuates ALT activation, while the maintenance of ALT telomere requires TRF1 and TRF2. POT1 and TPP1 can also influence the occurrence of ALT. The elucidation of how shelterin regulates the initiation of ALT remains elusive. This review presents a comprehensive overview of the current findings on the regulation of ALT by shelterin components, aiming to enhance the insight into the altered functions of shelterin components in ALT cells and to identify potential targets for the treatment of ALT tumor cells.
Topics: Telomere-Binding Proteins; Shelterin Complex; Telomere; Telomere Homeostasis; Telomerase; Telomeric Repeat Binding Protein 2
PubMed: 38069153
DOI: 10.3390/ijms242316830 -
Neuroscience and Biobehavioral Reviews Sep 2023Aging is characterized by functional decline occurring alongside changes to several hallmarks of aging. One of the hallmarks includes attrition of repeated DNA sequences... (Review)
Review
Aging is characterized by functional decline occurring alongside changes to several hallmarks of aging. One of the hallmarks includes attrition of repeated DNA sequences found at the ends of chromosomes called telomeres. While telomere attrition is linked to morbidity and mortality, whether and how it causally contributes to lifelong rates of functional decline is unclear. In this review, we propose the shelterin-telomere hypothesis of life history, in which telomere-binding shelterin proteins translate telomere attrition into a range of physiological outcomes, the extent of which may be modulated by currently understudied variation in shelterin protein levels. Shelterin proteins may expand the breadth and timing of consequences of telomere attrition, e.g., by translating early life adversity into acceleration of the aging process. We consider how the pleiotropic roles of shelterin proteins provide novel insights into natural variation in physiology, life history, and lifespan. We highlight key open questions that encourage the integrative, organismal study of shelterin proteins that enhances our understanding of the contribution of the telomere system to aging.
Topics: Humans; Adverse Childhood Experiences; Shelterin Complex; Telomere; Telomere-Binding Proteins; Proteins; Aging
PubMed: 37268182
DOI: 10.1016/j.neubiorev.2023.105261 -
Nucleic Acids Research Dec 2022Telomeres terminate with a 50-300 bases long single-stranded G-rich overhang, which can be misrecognized as a DNA damage repair site. Shelterin plays critical roles in...
Telomeres terminate with a 50-300 bases long single-stranded G-rich overhang, which can be misrecognized as a DNA damage repair site. Shelterin plays critical roles in maintaining and protecting telomere ends by regulating access of various physiological agents to telomeric DNA, but the underlying mechanism is not well understood. Here, we measure how shelterin affects the accessibility of long telomeric overhangs by monitoring transient binding events of a short complementary peptide nucleic acid (PNA) probe using FRET-PAINT in vitro. We observed that the POT1 subunit of shelterin reduces the accessibility of the PNA probe by ∼2.5-fold, indicating that POT1 effectively binds to and protects otherwise exposed telomeric sequences. In comparison, a four-component shelterin stabilizes POT1 binding to the overhang by tethering POT1 to the double-stranded telomeric DNA and reduces the accessibility of telomeric overhangs by ∼5-fold. This enhanced protection suggests shelterin restructures the junction between single and double-stranded telomere, which is otherwise the most accessible part of the telomeric overhang.
Topics: DNA; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 36511858
DOI: 10.1093/nar/gkac1176