Telomerase : dissecting the ends
Telomere syndromes are a group of pathologies associated with severely short telomeres that encompass dyskeratosis congenita, idiopathic pulmonary fibrosis, progeria, and aplastic anemia. Telomere shortening results from the inability of DNA polymerase to replicate the ends of chromosomes. Thereby, with time shortening chromosomes leads to cell senescence and apoptosis. To maintain telomere length, proliferating cells such as stem cells express telomerase ribonucleoprotein (RNP). Over 90% of cancer types are characterized by aberrant telomerase RNP expression. In contrast, inactivating mutations in the telomerase RNP can lead to telomere syndromes. The telomerase RNP consists of the telomerase reverse transcriptase (TERT) protein, the telomerase RNA (TR), Telomerase Cajal Body associated protein 1 (TCAB1), glycine-arginine rich protein 1 (GAR1), dyskerin, NOP10, NHP2 and H2A/H2B dimer. Loss of function mutations in the RNP, importantly TCAB1, are associated with telomere shortening in familial dyskeratosis congenita. TCAB1 maintains the telomere length by facilitating TR localization. Our work sheds light on the role and mechanism of TCAB1 in promoting telomerase RNP assembly by preventing phase-separation of TR with nucleoli, a sub-nuclear compartment, using a variety of approaches. We have shown that telomerase RNP assembly markedly diminished in the absence of TCAB1 through the compact nucleolar sequestration of TR in nucleoli. TR is stabilized by the nucleolar proteins DKC1, GAR1, NOP10 and NHP2. Our current work proposes that the conserved protein complex, known as the H/ACA complex, has a role in counteracting telomerase RNP assembly and trafficking and may play a role in RNA retention in nucleoli. In my dissertation, I will discuss what is known about the telomerase RNP, my contributions to the field, and future work toward unraveling the roles of the factors involved in the telomerase.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Klump, Basma Masraf
- Thesis Advisors
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Schmidt, Jens C.
- Committee Members
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Arnosti, David
Meek, Katheryn
Krishnan, Arjun
Robison, Alfred
- Date
- 2023
- Subjects
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Biology
Cytology
Molecular biology
- Program of Study
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Cell and Molecular Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- 129 pages
- ISBN
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9798379579487
- Permalink
- https://doi.org/doi:10.25335/rh1t-n746