ArticleThe Journal of biological chemistry2017
Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Trial
- Exploiting the Achilles' heel of cancer through a structure-based drug-repurposing approach and experimental validation of top drugs using the TRAP assay.Molecular diversity · 2025Article
- Genetic architecture of bone marrow fat fraction implies its involvement in osteoporosis risk.Nature communications · 2025Article
- TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders.NPJ genomic medicine · 2025Article
- A novel TERT variant associated with a telomere biology disorder and challenges in variant classification.EJHaem · 2025Article
- Recent progress in human telomerase structure and its therapeutic targeting.Frontiers in molecular biosciences · 2025Review
- [The characterization analysis of pathogenic T cells in immune-mediated aplastic anemia mouse model].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2022Article
- Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.Blood advances · 2022Article
- A structurally conserved human andProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes.Blood cancer journal · 2020Article
- Composition and Function of Telomerase-A Polymerase Associated with the Origin of Eukaryotes.Biomolecules · 2020Review
- Structural biology of telomeres and telomerase.Cellular and molecular life sciences : CMLS · 2020Review
- POT1-TPP1 telomere length regulation and disease.Computational and structural biotechnology journal · 2020Review
- Structural Biology of Telomerase.Cold Spring Harbor perspectives in biology · 2019Review
- Structure of Telomerase with Telomeric DNA.Cell · 2018Article
- Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase.Nucleic acids research · 2018Article
- Current Perspectives of Telomerase Structure and Function in Eukaryotes with Emerging Views on Telomerase in Human Parasites.International journal of molecular sciences · 2018Review
- Structural biology of telomerase and its interaction at telomeres.Current opinion in structural biology · 2017Review
- Molecular mechanisms of telomere biology disorders.The Journal of biological chemistryReview
- Multitarget anticancer profiling of Withania somnifera - Dual herbal combination with P. emblica, B. monnieri, and O. basilicum through integrated In silico docking and In vitro Jurkat cell line analysis.Journal of Ayurveda and integrative medicineArticle
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Authors and funding
3 authors at 1 institution in 1 country.
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Abstract
Naturally occurring mutations in the ribonucleoprotein reverse transcriptase, telomerase, are associated with the bone marrow failure syndromes dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis. However, the mechanism by which these mutations impact telomerase function remains unknown. Here we present the structure of the human telomerase C-terminal extension (or thumb domain) determined by the method of single-wavelength anomalous diffraction to 2.31 Å resolution. We also used direct telomerase activity and nucleic acid binding assays to explain how naturally occurring mutations within this portion of telomerase contribute to human disease. The single mutations localize within three highly conserved regions of the telomerase thumb domain referred to as motifs E-I (thumb loop and helix), E-II, and E-III (the FVYL pocket, comprising the hydrophobic residues Phe-1012, Val-1025, Tyr-1089, and Leu-1092). Biochemical data show that the mutations associated with dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis disrupt the binding between the protein subunit reverse transcriptase of the telomerase and its nucleic acid substrates leading to loss of telomerase activity and processivity. Collectively our data show that although these mutations do not alter the overall stability or expression of telomerase reverse transcriptase, these rare genetic disorders are associated with an impaired telomerase holoenzyme that is unable to correctly assemble with its nucleic acid substrates, leading to incomplete telomere extension and telomere attrition, which are hallmarks of these diseases.
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