Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point
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. Inhibitio...
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| Published in: | International journal of molecular sciences Vol. 20; no. 13; p. 3186 |
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| Format: | Journal Article |
| Language: | English |
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28-06-2019
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| Abstract | 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. |
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| AbstractList | 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. [...]the fact that telomerase is also active in tumor cells, contributing to their immortalization, could be turned into an advantage in the treatment of cancer if we could deactivate or slow down telomerase, specifically in tumor cells, we would be able to eradicate tumor cells more effectively. [...]this is in accordance with the general view that DNA-binding proteins associate with DNA nonspecifically at first and seek their recognition sequence and optimal binding site through specific interactions subsequently [15]. According to their electron microscopy experiments, there is approximately one shelterin complex per 100 bp of telomeric repeats [2]. Structure of TERT and TR The TERT catalytic core (1132 amino acids) consists of four major domains: the telomerase essential N-terminal (TEN) domain, the high-affinity RNA-binding domain (TRBD), the reverse transcriptase (RT) domain, and a C-terminal extension (CTE), analogous to a polymerase thumb [31,32,33]. |
| Author | Hofr, Ctirad Janovič, Tomáš Veverka, Pavel |
| AuthorAffiliation | LifeB, Chromatin Molecular Complexes, CEITEC and Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic |
| AuthorAffiliation_xml | – name: LifeB, Chromatin Molecular Complexes, CEITEC and Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic |
| Author_xml | – sequence: 1 givenname: Pavel surname: Veverka fullname: Veverka, Pavel organization: LifeB, Chromatin Molecular Complexes, CEITEC and Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic – sequence: 2 givenname: Tomáš surname: Janovič fullname: Janovič, Tomáš organization: LifeB, Chromatin Molecular Complexes, CEITEC and Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic – sequence: 3 givenname: Ctirad surname: Hofr fullname: Hofr, Ctirad email: hofr@sci.muni.cz organization: LifeB, Chromatin Molecular Complexes, CEITEC and Functional Genomics and Proteomics, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic. hofr@sci.muni.cz |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31261825$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
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| DOI | 10.3390/ijms20133186 |
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| Keywords | shelterin telomerase inhibitor telomere assembly protein-DNA interaction protein-protein interaction quantitative biology anticancer |
| Language | English |
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| Snippet | The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals.... [...]the fact that telomerase is also active in tumor cells, contributing to their immortalization, could be turned into an advantage in the treatment of... |
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| SubjectTerms | Animals anticancer Antineoplastic Agents - pharmacology assembly Binding sites Cancer Cell cycle Chromosomes Deoxyribonucleic acid DNA DNA-binding protein Domains Electron microscopy Enzyme Inhibitors - pharmacology Humans Immortalization inhibitor Microscopy Mutation Nucleotide sequence Protein Binding protein-DNA interaction protein-protein interaction Proteins quantitative biology Review RNA-directed DNA polymerase shelterin Telomerase Telomerase - antagonists & inhibitors Telomerase - chemistry Telomerase - metabolism telomere Telomere-Binding Proteins - chemistry Telomere-Binding Proteins - metabolism Tumor cells Tumors |
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| Title | Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point |
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