Linearization / Circularization of Chromosomes

[Mega [Andreas Stuermer]]

Hi everyone,

I read this, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796773/

The authors (there are many, some people seem to co-autorize all people they know :P ) have combined linear phage replication elements and a usual E. Coli chromosome and got it to be in a linear state.

There also was a newer experiment, http://pubs.acs.org/doi/abs/10.1021/sb400079u where they splited the circular genome in two linear ones. Replicates and grows without problems.


I guess that this is the opposite direction to longevity?
What about the opposite direction? Circularization of human chromosomes? So no telomerase is needed, no shortening of (non.-existent) telomeres?

In the future, I'm gonna try this in yeast, but it has 16 chromosomes :P Isn't there some eukaryote with, say, 2 chromosomes? :D

I guess some IPTG-induced Cre recombinase could cut out the selection marker 16 times...

Just waiting for gene synthesis to get cheaper.

[Koeng]

Maybe just try one chromosome. And also URA3 can be negatively selected for if that helps :)

-Koeng

[Mega [Andreas Stuermer]]

Ok, would be worth a try. Perhaps I would have to delete the centromere to be sure no linear DNA is replicated... URA3 is very nice, but won't be able to use 16 times - that's the goal in the end :D

[Matthew Pocock]

I think flys have just 4  chromosomes. However you probably want something easier to manipulate.

Matthew

Sent from my android - may contain predictive text entertainment.

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[Cathal Garvey (Phone)]

Need for telomerase isn't an accident. If it were a good idea to have active telomerase all the time, we would! But having a limit to replication limits the growth of premalignant tumours.

It's much easier to make telomerase constitutive than to circularise, if your only goal is "longevity".

"Mega [Andreas Stuermer]" <masters...@gmail.com> wrote:

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Sent from my Android device with K-9 Mail. Please excuse my brevity.

[Mega [Andreas Stuermer]]

Well, what about expressing telomerase in an inducible manner like with tet.?
And once a year you get a re-juvenation injection with tetracyclin. ^^

So circularization would do the same as constitutive telomerase expression?

[Cathal Garvey]

Well, sure, but every time you induce your many, many tiny benign
tumours will proliferate a little bit. So you also need to sort out how
to kill those guys between treatments.

To me, it seems likely that the model for cancer goes something like:
1) Lots of tiny benign tumours appear throughout life that escape
immune monitoring but hit the hayflick limit and do not become malignant
2) Some of these gradually mutate further and may become immortal
3) Of these, some will continue to escape immune system and become
larger benign tumours, or become malignant and become "cancer".

Some stuff suggests that you can target them early, if this model holds
true (and the "early escape" or "premalignant metastasis" hypotheses
back this model up). For example, there's meta-research suggesting that
even a temporary course of daily aspirin can reduce *lifelong* cancer
risk significantly; in the above model, this suggests that aspirin can
help kill these microtumours or early-escaped premalignancies, reducing
the risk of later further mutation and malignant-isation.

This may also be found true of other lifestyle-anticancer interventions
such as resveratrol/pterostilbene, berberine, etc.

So if you can solve the problem of microcancers and micrometastases,
you can probably also solve the long-term hazard of cancer due to
induction of telomerase, and therefore reduce its contribition to
ageing.

On Fri, 8 Nov 2013 02:02:03 -0800 (PST)

"Mega [Andreas Stuermer]" <masters...@gmail.com> wrote:

[Mega [Andreas Stuermer]]

>1) Lots of tiny benign tumours appear throughout life that escape
immune monitoring but hit the hayflick limit and do not become malignant
2) Some of these gradually mutate further and may become immortal
3) Of these, some will continue to escape immune system and become
larger benign tumours, or become malignant and become "cancer".

Sounds like natural selection.

Of course you could make the immune system more aggressive, but then it attacks your body parts (e.g. as in diabetics)
Do diabetics have less cancer btw?

[Joe Gorse]

On Fri, Nov 8, 2013 at 9:34 AM, Cathal Garvey <cathal...@cathalgarvey.me> wrote:

Well, sure, but every time you induce your many, many tiny benign
tumours will proliferate a little bit. So you also need to sort out how
to kill those guys between treatments.

Not necessarily. Giving the immune system more time to deal with the tumors in between the periods of the telomerase therapy may be sufficient in and of itself.

Cancer requires a certain amount of susceptibility to the genetic, metabolic, and systemic pre-conditions to facilitate oncogenesis. This tends to occur later in life as certain protection mechanisms degrade from the damages of aging and then the probability of getting cancer falls off in the late life for unexplained reasons.

Therefore adding another protection mechanism may be sufficient to significantly alter the landscape for cancer survival, particularly if it translatable to the clinic.

Cheers,

Joe

[Koeng]

Someone should try it in mice

[Joe Gorse]

For the carcinogen loaded environment we will simply house the mice in Ohio, neighbor to some poorly built fracked natural gas well. On second thought, that might be too cruel, so perhaps we could arrange to just ship some of our water to the vivarium.

Sent from my mobile phone

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[Koeng]

We need more people like you on this forum

[Andreas Stuermer]

>Someone should try it in mice

Yeah let's win the Methusalem prize :D Or having fun trying to do so.

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