The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres
| Autor: | Bradley A. Stohr, Amanda K. Frank, Duy C. Tran, Lifeng Xu, Roy W. Qu, David J. Segal |
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| Přispěvatelé: | Zhou, Jin-Qiu |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Telomerase lcsh:QH426-470 DNA Repair Telomere-Binding Proteins Biology Aminopeptidases Dyskeratosis Congenita Shelterin Complex Cell Line Telomerase RNA component Rare Diseases Telomere Homeostasis Cell Line Tumor Genetics medicine Humans Telomerase reverse transcriptase Gene Knock-In Techniques Telomeric Repeat Binding Protein 1 Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Molecular Biology Telomere Shortening Genetics (clinical) Ecology Evolution Behavior and Systematics Telomere-binding protein Tumor Tripeptidyl-Peptidase 1 Life Sciences Telomere HCT116 Cells medicine.disease Shelterin lcsh:Genetics Mutation Cancer research Serine Proteases Dyskeratosis congenita Developmental Biology Research Article |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 11, Iss 7, p e1005410 (2015) Frank, AK; Tran, DC; Qu, RW; Stohr, BA; Segal, DJ; & Xu, L. (2015). The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres. PLoS Genetics, 11(7), e1005410. doi: 10.1371/journal.pgen.1005410. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/5zb4c3d3 PLoS genetics, vol 11, iss 7 |
| ISSN: | 1553-7404 |
| Popis: | Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in the shelterin component TIN2 by introducing a TIN2-R282H mutation into cultured telomerase-positive human cells via a knock-in approach. The resulting heterozygous TIN2-R282H mutation does not perturb occupancy of other shelterin components on telomeres, result in activation of telomeric DNA damage signaling or exhibit other characteristics indicative of a telomere deprotection defect. Using a novel assay that monitors the frequency and extension rate of telomerase activity at individual telomeres, we show instead that telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. These observations suggest a direct role for TIN2 in mediating telomere length through telomerase, separable from its role in telomere protection. Author Summary The shelterin complex protects telomeres from being processed by the DNA damage repair machinery, and also regulates telomerase access and activity at telomeres. The only shelterin subunit known to promote telomerase function is TPP1, which mediates telomerase recruitment to telomeres and stimulates telomerase processivity. Mutations in shelterin components cause Dyskeratosis Congenita (DC) and related disease syndromes due to the inability to maintain telomere homeostasis. In this study, we have identified TIN2-R282H, the most common DC-causing mutation in shelterin subunit TIN2, as a separation-of-function mutant which impairs telomerase recruitment to telomeres, but not chromosome end protection. The telomerase recruitment defect conferred by TIN2-R282H is likely through a mechanism independent of TIN2’s role in anchoring TPP1 at telomeres, since TPP1 localization to telomeres is unaffected by the mutation. |
| Databáze: | OpenAIRE |
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