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Introduction to WILT

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6 replies to this topic

#1 John Schloendorn

  • Location:Mountain View, CA

Posted 10 June 2005 - 09:59 AM

Cell division in cancer
A life-threatening cancer contains billions of cells that are thought to originate from a single progenitor. During the evolution of cancer, multiple mutations (perhaps in the order of a dozen) have to arise, to gradually overcome our cells', bodies' and clinical therapys' multiple cancer defense mechanisms. Each of these mutations typically happens only in one or very few cells, that have to repopulate the entire tumor volume to confer the new genotype on it. In addition, tumor cells are constantly removed by the defense mechanisms themselves. Thus, the number of clone doublings that are required before a tumor can become life-threatening might plausibly be in the order of hundreds.
Such a massive amount of cell division has never been observed without a means to lengthen telomeres. Thus, it is thought that cancers cannot arise without lengthening their telomeres.

Telomeres and Telomerase
Telomeres are repetitive sequences at the ends of each of our chromosomes. They consist of hundreds to thousands of TTTAGGs repeats. Telomeres shorten with each cell division due to the so-called end-replication problem. When telomeres become critically short, they are thought to be recognized as a DNA single-stranded break, which causes the cell to remove itself from cell division by either apoptosis or senescence.
This is thought to limit the number of times most human somatic cells can double. Some cell types, including stem cells and germ cells make telomerase, an enzyme which lengthens telomeres. To prevent excessive lengthening, a partially characterized telomere length homeostatsis system is in place.
The mouse, unlike us, makes telomerase most body cells.

Some cancers do not express telomerase, but do lengthen their telomeres. They do this by a mechanism termed ALT. ALT is unfortunately not very well characterized. It seems to involve certain DNA repair factors and DNA-polymerase mediated, DNA template-dependent synthesis of telomeric repeats.

WILT (Whole-body Interdiction of Lengthening of Telomeres) proposes to delete the gene for telomerase, find a gene that is critical for ALT and delete it, too. Thus, telomeres could not be lengthened and cancers could not reach a life-threatening stage. No mutation could arise that rescues telomere lengthening, because the genes would be completely missing. Random mutations that generate whole genes out of thin air are thought to be way too unlikely to happen, even in the context of cancer.
As mentioned above, some cells in our bodies depend on telomerase. E.g. many rapidly dividing stem cells could not sustain their function without it. For example, this is important in the intestinal mucosa and the blood, the stem cells of which divide very rapidly to balance the rapid loss of cells in these organs. Thus, it is part of the WILT proposal to regularly reseed these tissues with fresh stem cells that have long telomeres, but no telomere lengthening mechanism.

Another brief introduction to WILT is here, the original paper is freely available here and a follow-up paper is also freely avaliable here.
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#2 123456 Re: Introduction to WILT

Posted 11 June 2005 - 02:24 AM

Informative post. When you said "TTTAGGs repeats" I am assuming you were referring to the Protein molecules Thymine, Adenine and Guanine; Where is Cytosine?, I thought that they paired up.
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#3 John Schloendorn Re: Introduction to WILT

  • Location:Mountain View, CA

Posted 11 June 2005 - 03:50 AM

That's right, the DNA is a double stranded molecule. The two strands run in opposite directions. By convention, you write only the strand that runs in the direction from from the 5' to the 3' end. (Because they're paired, adding the other strand would not add any new info.) If you write both strands (paired), a telomeric repeat would would look like:

5' ...TTTAGG... 3'
3' ...AAATCC... 5'

Most of the telomere looks like this, but the very last bits very close to the end of the chromosome (the t-loops) actually are single stranded. There is no C in these very outer regions. Oh, and that which the single letters stand for are called bases, rather than proteins.
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#4 123456 Re: Introduction to WILT

Posted 11 June 2005 - 12:38 PM

I think I understand now, thanks for the detailed explanation JS.
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#5 ag24 Re: Introduction to WILT

  • Location:Cambridge, UK

Posted 11 June 2005 - 12:58 PM

TTAGGG actually!
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#6 John Schloendorn Re: Introduction to WILT

  • Location:Mountain View, CA

Posted 12 June 2005 - 01:01 AM

Woops, sorry, varies with organism heh [bl:)]
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#7 rillastate Re: Introduction to WILT

Posted 22 July 2005 - 12:28 PM

So that's what WILT is. I came across that word in one of your posts last week and was like, "what's that."

Like 123456 said; Thanks for the explanation.
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