telomeres and cancer.txt

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telomeres and cancer.txt
2012-03-26 14:37:42
telomeres cancer

cancer and telomeres
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  1. Components of catalytic core
    • Made up of:
    • 1. Integral Telomerase RNA (TR)
    • 2. Telomerase Reverse Transcriptase (TERT)
    • These 2 components needed for TELOMERASE ACTIVITY
  2. 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
  3. 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
  4. Telomerase Reverse Transcriptase (TERT)
    • protein and catalytic component of core telomerase enzyme
    • main fxn in add'n of nucleotides or elongation of telomere ends
  5. 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
  6. 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
  7. 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
  8. 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.
  9. 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
  10. 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
  11. Telomerase inhibition
    • results in loss of telomeric DNA and apoptosis
    • telomere dysfunction 1st promotes chromosomal instability that drives early carcinogenesis