Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1
| Autor: | Kathleen Collins, John M. Boyle, Kelsey M. Hennick, Xiaozhu Zhang, Samuel G. Regalado, Jacob M. Vogan, Dirk Hockemeyer |
|---|---|
| Přispěvatelé: | Lechler, Terry |
| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
Pluripotent Stem Cells Telomerase Mutant Telomere-Binding Proteins Biology Regenerative Medicine medicine.disease_cause Medical and Health Sciences Shelterin Complex 03 medical and health sciences Rare Diseases 0302 clinical medicine Genetics medicine 2.1 Biological and endogenous factors Humans Protein Isoforms Aetiology Induced pluripotent stem cell Molecular Biology 030304 developmental biology 0303 health sciences Mutation Tripeptidyl-Peptidase 1 Nuclear Functions Telomere Homeostasis Articles Cell Biology Telomere Biological Sciences Stem Cell Research Shelterin Phenotype Cell biology Cell culture Hela Cells Stem Cell Research - Nonembryonic - Non-Human Generic health relevance Stem cell 030217 neurology & neurosurgery HeLa Cells Developmental Biology |
| Zdroj: | Molecular biology of the cell, vol 31, iss 23 Molecular Biology of the Cell |
| Popis: | Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control. We demonstrate that cells deficient for TPP1S (TPP1S knockout [KO]), as well as the complete TPP1 KO cell lines, undergo telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres, while TPP1 KO cells die. We compare these phenotypes with those of TPP1L104A/L104A mutant cells, which have short and stable telomeres similar to the TPP1S KO. In contrast to TPP1S KO cells, TPP1L104A/L104A cells respond to increased telomerase levels and maintain protected telomeres. However, TPP1L104A/L104A shows altered sensitivity to expression changes of shelterin proteins suggesting the mutation causes a defect in telomere length feedback regulation. Together this highlights TPP1L104A/L104A as the first shelterin mutant engineered at the endogenous locus of human stem cells with an altered telomere length set point. |
| Databáze: | OpenAIRE |
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