ArticleThe Journal of biological chemistry2016
Multiple Mechanisms Contribute to the Cell Growth Defects Imparted by Human Telomerase Insertion in Fingers Domain Mutations Associated with Premature Aging Diseases.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Telomerase structural biology comes of age.Current opinion in structural biology · 2022Review
- Research Progress on the Effect of Traditional Chinese Medicine on Signal Pathway Related to Premature Ovarian Insufficiency.Evidence-based complementary and alternative medicine : eCAM · 2022Review
- A structurally conserved human andProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural biology of telomeres and telomerase.Cellular and molecular life sciences : CMLS · 2020Review
- Structure of Telomerase with Telomeric DNA.Cell · 2018Article
- Structural biology of telomerase and its interaction at telomeres.Current opinion in structural biology · 2017Review
- Progress in Human and Tetrahymena Telomerase Structure Determination.Annual review of biophysics · 2017Review
- Telomerase Regulation from Beginning to the End.Genes · 2016Review
- Molecular mechanisms of telomere biology disorders.The Journal of biological chemistryReview
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Normal human stem cells rely on low levels of active telomerase to sustain their high replicative requirements. Deficiency in telomere maintenance mechanisms leads to the development of premature aging diseases, such as dyskeratosis congenita and aplastic anemia. Mutations in the unique "insertion in fingers domain" (IFD) in the human telomerase reverse transcriptase catalytic subunit (hTERT) have previously been identified and shown to be associated with dyskeratosis congenita and aplastic anemia. However, little is known about the molecular mechanisms impacted by these IFD mutations. We performed comparative functional analyses of disease-associated IFD variants at the molecular and cellular levels. We report that hTERT-P721R- and hTERT-R811C-expressing cells exhibited growth defects likely due to impaired TPP1-mediated recruitment of these variant enzymes to telomeres. We showed that activity and processivity of hTERT-T726M failed to be stimulated by TPP1-POT1 overexpression and that dGTP usage by this variant was less efficient compared with the wild-type enzyme. hTERT-P785L-expressing cells did not show growth defects, and this variant likely confers cell survival through increased DNA synthesis and robust activity stimulation by TPP1-POT1. Altogether, our data suggest that multiple mechanisms contribute to cell growth defects conferred by the IFD variants.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.