Telomerase
2015-06-19azim58 - Telomerase
Telomerase portal
Facts about telomerase
http://www4.utsouthwestern.edu/cellbio/shay-wright/intro/facts/sw_facts.htm
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an example telomere repeating sequence: TTAGGG
telomere length: can be up to about 15,000 bp; in humans average telomere length is 10-15 kb (ref Telomere Shortening in Human Diseases)
telomere loss per cell division: about 25-200 bp; 50-200 bp (ref Telomere Shortening in Human Diseases); 71-71 bp/year in lymphocytes (High-throughput telomere length quantification by
FISH and its application to human population studies)
Critically short length of telomeres: about 77 bp (1)
- 1: paper: The nature of telomere fusion and a definition of the critical telomere length in human cells
- -see also what is the critical short length of telomeres
telomerase 10-20X more active in cancer cells
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Structure of telomerase
Nice paper on structure of telomerase
- "C:\Users\Kurt Whittemore\Box Sync\DocDR\2014\09-22-2014d0952\A solution to the telomerase puzzle.pdf"
- -University of California Santa Cruz 2013
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books about telomerase
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historical figures involved with telomerase discoveries
- Herman Muller, Elizabeth Blackburn, August Weissmann (around 1881),
diseases associated with faulty telomerase holoenzyme complex or faulty telomeres
- dyskeratosis congenita is caused by a mutation in the dyskerin protein.
- Acquired aplastic anaemia
- Idiopathic pulmonary fibrosis (IPF)
- Cartilage hair hypoplasia (CHH)
- Bloom syndrome
- ataxia-telangiectasia
- Nijmegen breakage syndrome
- Fanconi anemia
components of telomerase holoenzyme
- TERT (protein part)
- -the TERT protein has at least different isoforms (3)
- TERC or TR (RNA part)
- DKC1
- other proteins?
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- here's a diagram of some other proteins interacting with TERT at the
http://www.stanford.edu/group/artandi/telomerase.htm
Super-active telomerase exists (Julian Chen at ASU has worked with this)
centenarians and their offspring have longer telomeres compared to the
telomeres of the whole population on average
Interaction of telomerase with other proteins?
If I remember correctly, telomerase can interact with other proteins to
turn other genes on and off as well. I would be interested to know what
other types of proteins and/or transcription factor proteins telomerase
interacts with to do this. Can telomerase act as a transcription factor
itself? I don't know.
- Telomerase interacts with quite a few other proteins. see
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- TERT involved in Wnt signaling Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins
- TERT acts as a RNA polymerase Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins
- TERT involved in stem cell mobilization Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins
TERT Complexes
hTERT+hTERC -> telomerase activity -> telomere maintenance
hTERT+RMRP -> RdRP activity -> chromatin maintenance?
hTERT+BRG1 -> regulation of Wnt/beta-catenin signalling -> stem cell maintenance
hTERT + other proteins? -> other activities? -> other functions?
- Section 8.4 of Telomerase: Chemistry, biology, and clinical applications
Factors affecting telomerase transcription?
There are many factors that can influence the level of expression of
telomerase in a cell. For example, I know that estrogen even binds to
proteins which then either directly or indirectly influence how proteins
bind to the promoter of telomerase and upregulate or downregulate
telomerase expression. There are many other compounds besides estrogen
that have an influence. I wish I knew much more about this.
Post-translational modifications of telomerase
Does telomerase get phosphorylated at various sites to enhance or reduce
various functions as many other proteins do?
Yes it does. Some of the phosphorylation sites can be found here
http://www.phosphosite.org/proteinAction.do;jsessionid=71C94B3261C802ED99FA
94C29B195611?id=3829&showAllSites=false
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companies that claim to lengthen or maintain telomeres
Some research papers on telomerase portal 6-14-13
Organizations to measure telomeres
Telomerase Research Paper by Mara
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Telomerase expression not sufficient to maintain telomere length in cells and stem cells
- Telomere and telomerase in stem cells paper (British journal of cancer 2007)
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Effect of telomerase in quiescent non-dividing cells
- Telomere dysfunction induces metabolic and mitochondrial compromise
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Do cancer cells have long or short telomeres?
- According to Marinela Mendez, normal tumor cells have short telomeres because they divide so fast. Cancer stem cells have super long telomeres
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Questions
- Why do K5-mTERT mice (telomerase overexpressing mice) develop more tumors, but then mice treated with telomerase gene therapy or mice that have telomerase activated after turning on a genetic switch (like in the Harvard paper titled "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice") do not? Is it just because in the K5-mTERT mice the overexpression is constant, and in the other two cases it is temporary overexpression?
- -Perhaps the gene therapy mice don't get cancer because the AAVTERT is diluted out when cells proliferate...
See also