Damage to chromosomes and temperature

[sontag]

Do errors in chromsome replication increase
as the temperature of a cell increases?
Also can a cell regulate its temperature and keep it
different to the extracellular medium surrounding it?

 

[iansmith]

As far as I remember, temperature does not alter the error frequency of DNA polymerase. Temperature will, however, have an effect on the rate of DNA replication.

Cell cannot regulate their temperature; however, they sense a difference in temperature and express the appropriate proteins that are stable and more active at specific temperature range.

 

[Monique]

Yes, errors increase with temperature. Enzymes from organisms living in high temperature environments are used in the lab for their high fidelity.

I don't think a cell can regulate its temperature, an organism can.

 

[sontag]

IAN SMITH:
Cell cannot regulate their temperature; however, they sense a difference in temperature and express the appropriate proteins that are stable and more active at specific temperature range.

Can you give an example of this?

MONIQUE:
If errors increase with temperature and cells can't
regulate their temperature then isn't it possible that
cancer cells are cells which get too hot,perhaps
because of chemical reactions or other factors.

 

[iansmith]

Do a search for heat shock protein and you should find several example

A few example
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15782306
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15852341

 

[Monique]

If errors increase with temperature and cells can't
regulate their temperature then isn't it possible that
cancer cells are cells which get too hot,perhaps
because of chemical reactions or other factors.

No, cancer cells fail to do their proper cell cycle checks and thus continue to replicate even though there are errors present. A normal cell would sense the errors, stop to repair them or go into perminant senescense.

 

[iansmith]

You may want to look at this

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=849445

The error rates at 37 degrees C for the complete system were as follows:: B. licheniformis: dATP, 1/61; dCTP, 1/830; dGTP, 1/360; dTTP, 1/65; B. stearothermophilus: dATP, 1/68; dCTP, 1/1430; dGTP, 1/440; dTTP, 1/67. For both organisms, the error rate for dCTP and dGTP was independent of incubation temperature; the error rate for dATP and dTTP was 5-50-fold greater than that for dCTP or dGTP and increased significantly from 37 to 55 degrees C.

http://www.jbc.org/cgi/reprint/250/12/4405

The rate of polymerization was greater at higher temperatures and approximately doubled for every 10 degrees increase. The error rate was constant at all temperatures.

 

[Monique]

Really, I would have expected that the proof-reading ability or fidelity would have been better for polymerases from organisms living at high temperatures but I don't really have literature on that besides the following.

One of the most discussed characteristics of thermostable polymerases is their error rate. Error rates are measured using several different assays, and as a result, estimates of error rate vary, particularly when the assays are performed by different labs. As would be expected from first principles, polymerases lacking 3'->5' exonuclease activity generally have higher error rates than the polymerases with exonuclease activity. The total error rate of Taq polymerase has been variously reported between 1 x 10-4 to 2 x 10-5 errors per base pair. Pfu polymerase appears to have the lowest error rate at roughly 1.5 x 10-6 error per base pair, and Vent is probably intermediate between Taq and Pfu.

 

[sontag]

MONIQUE:
No, cancer cells fail to do their proper cell cycle checks and thus continue to replicate even though there are errors present. A normal cell would sense the errors, stop to repair them or go into perminant senescense

SONTAG:And what if heat has damaged the cell cycle checkers?

IAN SMITH:
the error rate for dATP and dTTP was 5-50-fold greater than that for dCTP or dGTP and increased significantly from 37 to 55 degrees C.

SONTAG:
What is the explanation for these differences?

 

[kalladin]

When a cell is under heat stress, I believe all protein and nuclear machinery shut down except for those required to synthesize heat shock proteins. In other words, there would be no cell growth/division and any damage to cell cycle regulators would have no effect. On a side note, heat shock proteins are synthesized by the cell so that they can repair any damaged proteins resulting from heat.

 

[sontag]

KALLADIN:
On a side note, heat shock proteins are synthesized by the cell so that they can repair any damaged proteins resulting from heat.

SONTAG:
What sort of damage is repaired and how is this done?
Presumably proteins lose their specific shapes and some atoms?

 

[kalladin]

Some heat shock proteins if not all, have chaperone abilities. They are like a magic box... you put in a damaged protein and the box folds it into the correct shape and releases the repaired protein. Heat usually induces denaturation of the protein where there is incorrect conformational structure.

 

[sontag]

I found on the web at http://www.antigenics.com/products/tech/hsp/
that HSPs are bound to peptides and the bound system is released into the bloodstream when some cells die,eliciting an immune response by binding to the CD91 receptor on macrophages.Can be an early warning to the immune system of cancer.A good article on chaperones and cancer here:
http://images.google.co.uk/imgres?i...heat+shock+protein%22&hl=en&lr=&ie=UTF-8&sa=G

 

[Monique]

Can be an early warning to the immune system of cancer.

You first have to establish whether in cancer cells are under heat stress, you haven't shown any evidence for that yet.

A good article on chaperones and cancer here:
http://images.google.co.uk/imgres?i...heat+shock+protein%22&hl=en&lr=&ie=UTF-8&sa=G

That is just an image, not an article. The following has nothing to do with heat per se, but in cancer cells you can expect that there is a very large proportion of incorrectly folded proteins: just because it has to synthesize proteins very fast.

You see this during virus infection. In short: there are two types of proteins ubiquitinated and degraded by the proteosome; 1) retirees, which are old proteins that have been around for a long time and 2) DRiPS, which stands for defective ribosomal products. During a viral infection (and thus rapid protein production) you see an increase in DRiPS. It is known that those DRiPS are degraded rapidly and that they are a major source of MHCI presentation. This is a smart system: if a cell is infected with an virus, the proteins will be quickly presented and the cell will be killed.

You can think that the same might happen in a tumor cell, where there is an increase in DRiPS. The only problem is that the DRiPS are autologous, so the immune system should not recognize them

 

[sontag]

in cancer cells you can expect that there is a very large proportion of incorrectly folded proteins: just because it has to synthesize proteins very fast.

Why does a fast speed result in more errors.And why do dATP and dTTP have
5-50 times the error rate of dGTP and dCPT for bacteria that live in hot water
(see post above).

You can think that the same might happen in a tumor cell, where there is an increase in DRiPS. The only problem is that the DRiPS are autologous, so the immune system should not recognize them

Would there be a higher density of DRiPs expressed on the cell surface
and is there any chemical process in the body that would be affected by this
higher density?

 

[Monique]

Why does a fast speed result in more errors.And why do dATP and dTTP have
5-50 times the error rate of dGTP and dCPT for bacteria that live in hot water
(see post above).

I was talking about protein folding, folding is a difficult process molecularly. In the ER this protein folding takes place in the accompaniment of chaparones, correct folding is checked by certain proteins. If the protein production is really fast, there is more room for error and there are not enough chaparones or error-read proteins to check the process.

I'm not sure why adenosine or thymine have a higher error rate, a suggestion would be that they only form two hydrogen bridges, whereas guanine and cytosine produces three.

Would there be a higher density of DRiPs expressed on the cell surface
and is there any chemical process in the body that would be affected by this
higher density?

If more DRiPS are produced, their representation will be increased relative to the presentation of other cellular proteins. This higher density of presentation of DRiPS by MHCI (immune presentation) will give immune cells information about what is going on inside that particular cell. If the cell all of a sudden starts to present a lot of misfolded melanin (in case of melanoma), the cell will recognize this protein as foreign (since the body is not used to seeing melanin), natural killer cells will be attracted by the presented melanin, which subsequently will kill the cell.

 

[sontag]

This links explains that the extra hydrogen bond for C-G is part of the reason for
the lower error rate in transcription compared to A-T.Deoxynucleotides are in chemical equilibrium with the template strand and C-G is the combination most likely
to be present at a C or G location when DNA polymerase reaches that location.

"there are various thermodynamic and steric considerations that drive the formation of basepairs, such that the most stable pairing will have the most hydrogen bonds with the best fit."

http://www.madsci.org/posts/archives/2001-11/1004743083.Bc.r.html

 

[Monique]

Sontag, you can quote someone either by hitting the quote button (bottom right of every post) or by putting the text between the following code:

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or
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where instead of these brackets () you use these []

 

[sontag]

Sontag, you can quote someone either by hitting the quote button (bottom right of every post) or by putting the text between the following code:

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[quote =sontag]The quote button worked![/quote]