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Components of catalytic core
- Made up of:
- 1. Integral Telomerase RNA (TR)
- 2. Telomerase Reverse Transcriptase (TERT)
- These 2 components needed for TELOMERASE ACTIVITY
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Integral Telomerase RNA (TR)
- This is NON-coding RNA
- Provides template for telomere repeat sequences and motifs
- Roles:
- 1. binding catalytic TERT protein and various telomerase acessory proteins
- 2. Defining template boundary
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TR structure
- 3 main domains
- 1. template pseudoknot domain, aids in TERT binding and telomerase function
- 2. CR 4/5 domain
- 3. H/ACA domain, binding site for proteins
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Telomerase Reverse Transcriptase (TERT)
- protein and catalytic component of core telomerase enzyme
- main fxn in add'n of nucleotides or elongation of telomere ends
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TERT structure
- 4 domains
- 1. Telomerase essential N-terminal domain
- 2. Telomerase RNA binding domain
- 3. Reverse transcriptase domain
- 4. C-terminal extension (CTE), aids DNA binding by associating w/phosphodiester backbone of DNA/RNA hybrid
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Structure and function of TERT
- CTE: aids DNA binding by associating w/phosphodiester backbone of DNA/RNA hybrid
- RNA-interacting domain 2: binding site for TR CR 4/5 domain
- Motifs: finger motifs 1 & 2, bind incoming nucleotides
- palm motif A & E: form catalytic site
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Telomere shortening and associated diseases
- shortened telomeres due to exhaustive replicative capacity
- inflammatory cytokines and growth factors cause activation of nearby cells --> interferes with normal tissue function
- Result in shortened telomeres
- responsible for:
- 1. Dyskeratosis congenita
- 2. Idiopathic Pulmonary Fibrosis
- 3. Cancers
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Dyskeratosis congenita
- Inherited X-linked disease, rare disease (1 in 1mil), death at 16 median age
- Causes of death are bone marrow failure, pulmonary disease and cancer
- Dyskerin: involved in making ribosomes and pre-mRNA splicing, along with other protein formation. Patients with mutation in dyskerin or other associated proteins may have reduced TERC levels. Mutation in TERT also in DKC
- These mutations in TERT or TERC genes result in shorter telomere lengths.
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Idiopathic Pulmonary Fibrosis
- fatal lung disease
- Diagnosis age 50, lifespan of 2-4 years after diagnosis
- TERT and TERC mutations (ie, nucleotide deletions to make frameshifts and truncated proteins) associated w/IPF
- these mutations cause shorter telomere lengths of circulating WHITE BLOOD CELLS
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Cancer
- each round of cell division results in DECREASED telomeres
- stem cells proliferate and telomerase shortening occurs, but the premature exhaustion of these stem cells leads to pulmonary fibrosis or other diseases (DKC), bone marrow failure
- Mutations in Cell cycle checkbone genes (ie p53) growth of cells continues and telomeres continue to shorten until they cannot protect chromosome ends.
- This can lead to cancer
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Telomerase inhibition
- results in loss of telomeric DNA and apoptosis
- telomere dysfunction 1st promotes chromosomal instability that drives early carcinogenesis
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