DNA strands often 'wiggle' as part of genetic repair

November 5, 2015, Rockefeller University
DNA strands often 'wiggle' as part of genetic repair

Sometimes, the molecules that make up life exhibit strange behavior. For instance, in simple organisms such as yeast, when genetic material becomes damaged, the affected DNA strands increase their motion, waving about inside the cell like a sail unfurled.

Over the years, scientists have seen more instances of such curious behavior during DNA repair—one of life's most fundamental processes—but whether it also happened in human cells was debated. Until now.

New research by Rockefeller University scientists shows the swaying of strands is, in fact, a pervasive part of DNA repair in . Titia de Lange, the Leon Hess Professor and head of the Laboratory of Cell Biology and Genetics, led the study, which was described November 5 in Cell.

"This paper shows that an increase in physical mobility of DNA strands is something that happens inside mammalian cells every time there is a break in the DNA," says de Lange, who is also American Cancer Society Professor, and Director of the Anderson Center for Cancer Research at Rockefeller. "These breaks—and the subsequent increase in DNA mobility—can happen as a result of problems during DNA replication, chemotherapy, and other causes."

By learning more about this intriguing mechanism, the researchers hope to find new ways to optimize our use of cancer treatments, some of which act by manipulating the DNA repair process in malignant cells.

For many years, biologists hotly debated how common it was for DNA to become more mobile following damage. In 2008, de Lange and her team detected the process in telomeres, the caps on the ends of chromosomes, by filming DNA before and after damage occurred. This was a key finding, as telomeres serve important functions in cell division and protecting mammalian chromosomes.

Every time a double-strand break in DNA occurs, the damaged ends move about during repair (left). The squiggly lines represent the movement of individual DNA ends. This mobility is drastically reduced in the presence of the chemotherapy drug Taxol (right). Credit: Laboratory of Cell Biology and Genetics at The Rockefeller University

Since that study, de Lange and postdoctoral fellow Francisca Lottersberger in her lab have identified the cellular structures involved in increasing DNA mobility after damage. One of those structures is embedded in the , the barrier surrounding the chromosomes. Surprisingly, the second structure that boosts mobility in damaged DNA—microtubules—resides outside the nucleus, in the cytoplasm. Microtubules are highly dynamic rods that can move things around inside the cell, but can also poke the nucleus. Somehow, the microtubules interact with the nuclear envelope to send a signal to increase mobility of damaged DNA.

With these discoveries, de Lange and her team had the tools to determine the pervasiveness of DNA mobility in the mammalian genome—by deleting the structures it depended upon. When the team deleted the envelope protein, double-stranded breaks in DNA throughout the genome became less mobile. The same occurred when the researchers added drugs that inhibit microtubules.

The next step, de Lange says, is to try to find out why DNA mobility increases following damage. One possibility, she proposes, is that the process serves as a "fail-safe mechanism" when normal repair processes don't work: The more the broken strands move around, the bigger the chances are of them finding each other again, and repairing the break.

But this process is dangerous when many DNA breaks occur at once—such as after exposure to chemotherapy. In this situation, the movement of broken ends can cause pieces from different chromosomes to stick together, forming monster chromosomes that kill the cell. This principle underlies the treatment of certain forms of breast and ovarian cancer with new drugs called PARP inhibitors, which cause many DNA breaks at once.

But now that de Lange has shown that microtubules are needed for this process, it points to a potential problem if doctors combine PARP inhibitors with another type of chemotherapy that is often prescribed in these cancers, Taxol (paclitaxel)—which kills cells by disrupting the function of microtubules. Without microtubules, damaged DNA ends are less mobile, and less likely to form monster chromosomes. So, the effect of one drug may counteract the other.

"Although we are investigating a very basic problem in biology—how cells repair DNA damage —our discoveries have potential ramifications in the clinic," says de Lange.

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JVK
2.8 / 5 (9) Nov 05, 2015
This is another report from serious scientists who realize the need to address RNA-mediated DNA repair at all levels of investigation. The levels include biophysically constrained protein folding chemistry, which links top-down causation from nutrient energy-dependent base pair changes and amino acid substitutions to the stability of organized genomes.

Fixed substitutions are linked to cell type differentiation in all living genera by what is currently known about the conserved molecular mechanisms of nutrient-dependent pheromone-controlled physiology of reproduction in species from microbes to man.

It is past time for everyone to have fun ridiculing the evolutionary theorists who continue to place the bioenergenic costs of cell type differentiation into their ridiculous theories about how random genetic drift somehow leads to the biodiversity manifested in morphological and behavioral phenotypes as if they emerged in the context of mutations and evolution.
Captain Stumpy
2.5 / 5 (8) Nov 05, 2015
It is past time for everyone to have fun ridiculing the evolutionary theorists
@jk
umm...
1- the Theory of Evolution is backed by validated evidence

2- from one of your own links you posted here: http://phys.org/n...lls.html

We are a multidisciplinary society, representing molecular, evolutionary and structural biology, biochemistry, biomedical sciences, chemistry, genetics, and virology as they relate to questions of the structure and function of RNA and of ribonucleoprotein assemblies
http://www.rnasoc...society/

this means, by definition, you will have theorists involved to develop testable hypothesis for experimentation

if you were aware of the scientific method, you would know that
https://en.wikipe...c_method

http://media-cach...f521.jpg

anonymous_9001
3 / 5 (6) Nov 05, 2015
the movement of broken ends can cause pieces from different chromosomes to stick together, forming monster chromosomes that kill the cell.


Look at that, Kohl. Detrimental chromosomal rearrangements.
JVK
3 / 5 (8) Nov 05, 2015
Look at that, Kohl. Detrimental chromosomal rearrangements.


How can anyone not realize the difference between nutrient-dependent chromosomal rearrangements in all vertebrates and virus-driven genomic entropy manifested in detrimental chromosomal rearrangements?

I think that Andrew Jones (aka anonymous_9001) should join Dr. Ben Carson's campaign team as their official biologically uninformed science idiot -- if Richard Dawkins or PZ Myers refuses the position.

Does anyone think that Jones is under qualified? He has an undergraduate degree in biology. Should he be required to gain a Ph. D in something to prove he is an over-educated science idiot?
anonymous_9001
2.7 / 5 (7) Nov 05, 2015
How can anyone not realize the difference between nutrient-dependent chromosomal rearrangements in all vertebrates and virus-driven genomic entropy manifested in detrimental chromosomal rearrangements?


Just as you're unable to explain the mechanism/enzymatic pathway differences between mutations and amino acid substitutions, you won't be able to explain the difference here either.
JVK
3 / 5 (8) Nov 05, 2015
I've explained the difference in the context of nutrient-dependent base pair changes, amino acid substitutions, and chromosomal rearrangements, and I provided you with an example: white-throated sparrow morphs before I did that.

You should admit that you want to always be a biologically uninformed science idiot who decided to harass a medical laboratory scientist with 40 years testing experience in clinical laboratories based on what you learned from your mutagenesis experiments -- YOU MORON!

JVK
3 / 5 (8) Nov 06, 2015
See also: http://medicalxpr...tal.html

The link from the sun's anti-entropic energy to the de novo creation of olfactory receptor genes and nutrient-dependent RNA-mediated amino acid substitutions that differentiate the cell types of all living genera by protecting them from virus-driven genomic entropy is clear.

The only way for biologically uninformed science idiots to continue with their ridiculous claims about how mutations lead to evolution is to eliminate the consideration for nutrient energy-dependent changes. That's how the sudden jumps in energy that de Vries defined as mutations can be used to destroy any logical attempt to link nutrients to the physiology of reproduction and biophysically constrained biodiversity.

In "The bioenergetic costs of a gene" the costs are replaced with claims about "...the power of random genetic drift..." http://www.pnas.o...abstract
JVK
3 / 5 (8) Nov 06, 2015
See also: Using evolution to better identify cell types http://www.scienc...18.short

Gunter Wagner's claim is that you do not understand cell types "...until one understands that they are evolved entities," .... Pavlicev agrees: "I think [the evolutionary approach] will eventually take over, because it appears to offer strong explanatory power."

Strong explanatory power is attributed to a 1904 definition of energy jumps. The jumps lead to the understanding of evolved cell type differences outside the context of the nutrient-dependent biophysically constrained chemistry of RNA-mediated gene duplication and RNA-mediated amino acid substitutions. The substitutions that differentiate all cell types in all individuals of all living genera via the physiology of reproduction that transgenerationally protects supercoiled DNA from virus-driven genomic entropy are replaced by the definition of "mutation."
Captain Stumpy
2.3 / 5 (6) Nov 09, 2015
a medical laboratory scientist with 40 years testing experience in clinical laboratories
@jk
1- argument from authority is a logical fallacy, especially when you are not an authority
2- so now you change your life from 40+ years as a diagnostician?
3- being a chronic liar only undermines your argument, especially if you want to argue from your perceived authority

not being able to validate said authority with proof makes your claim an unsubstantiated conjecture, except that, technically speaking, it is a FALSE claim as you've demonstrated you are not educated, licensed or in any way the authority you claim to be
http://www.auburn...ion.html

The only way for biologically uninformed science idiots to continue with their ridiculous claims about how mutations lead to evolution
wait... but YOU have stated that your model causes mutations, so YOU also claim that mutations lead to evolution
shall i quote it again?
JVK
3 / 5 (8) Nov 09, 2015
YOU have stated that your model causes mutations, so YOU also claim that mutations lead to evolution


Your ridiculous claims about what I have stated or what I have claimed can be viewed in the context of my atoms to ecosystems model, which I claim links nutrient-dependent pheromone-controlled cell type differentiation in species from microbes to man.

Nutrient-dependent RNA-mediated DNA repair takes the "wiggle room" out of genome organization and the "weasel words" out of neo-Darwinian theory via clear examples of differences between virus-driven genomic entropy and nutrient-dependent stability of organized genomes that is achieved only via the biophysically constrained chemistry of protein folding in species from microbes to humans.

The clear examples were included in a series of my published works during the past 20 years.
Captain Stumpy
2.3 / 5 (6) Nov 09, 2015
Your ridiculous claims about what I have stated or what I have claimed
So, you're claiming you didn't post the following
[ME]remember when I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
(this is the DEFINITION of mutation) to which you [jk] answered
YES!
--Thanks for asking
you can see where i've historically given you links (on feb 22, 2014) that show the modern definitions of Mutation, proven and validated: http://phys.org/n...lts.html

to which you also ignored...

.

so are you now saying that this is all someone else?
you are saying you didn't say this?
that it isn't your reply?

well, then!!
call a lawyer and litigate for libel!
i would love to go to court against you!

(PS- i can prove you're a liar. evidence is important in court and science)

JVK
3 / 5 (8) Nov 09, 2015
i would love to go to court against you!


You are too ignorant to challenge anyone to a court battle over anything. Only the most biologically uninformed science idiots of all those throughout history would continue to attack me or the model that links atoms to ecosystems via RNA-mediated amino acids substitutions and DNA repair unless they had an alternative model.

The fact that you simply followed in the footsteps of PZ Myers and Andrew Jones and based your attacks on their claims attests to how one biologically uninformed science idiot can teach many more to become or to remain biologically uninformed science idiots because the idiots are too stupid to ever ask "Is there a model for that?"

Models of cell type differentiation are All About that Base (Meghan Trainor Parody) https://www.youtu...youtu.be and about RNA-mediated amino acid substitutions. http://youtu.be/DbH_Rj9U524

JVK
3 / 5 (8) Nov 09, 2015
See also: http://medicalxpr...lls.html Molecular clocks control mutation rate in human cells

This suggests acquisition of the mutations is like magic, despite experimental evidence that it is biophysically constrained during thermodynamic cycles of protein biosynthesis and degradation that link microRNAs from amino acid substitutions and adhesion proteins to protection of organized genomes from virus-driven genomic entropy.

See: Histone-modifying proteins, not histones, remain associated with DNA through replication http://phys.org/n...ion.html

This suggests virus-driven genomic entropy is biophysically constrained by RNA-directed DNA methylation in the context of nutrient-dependent organism-level thermoregulation and homeostasis.

Is there an evolutionary theorist willing to reassert claims about how de novo methylation links mutations to molecular clocks?
Captain Stumpy
2.3 / 5 (6) Nov 09, 2015
You are too ignorant to challenge anyone to a court battle over anything
@jk
ROTFLMFAO
does this mean you aint gonna try litigation for libel?

or does this mean you are admitting you posted the above answer to my inquiry about your model?
The fact that you simply followed in the footsteps of PZ Myers and Andrew Jones
1- their arguments against your creationist stupidity (& homophobia, & prejudice) and lack of biological comprehension are based upon fact and evidence that is VALIDATED: you have YET to be able to refute with factual evidence or even references that support your claims (to date: you have a 100% fail rate WRT interpreting the studies)
http://www.auburn...ion.html

2- if you're calling me an idiot for that, then i stand in incredibly great company, including, but not limited to, almost ALL biologists and medical professionals (the actual ones, licensed and certified- not the frauds like you)
Captain Stumpy
2.3 / 5 (6) Nov 09, 2015
@jk cont'd
All About that Base (Meghan Trainor Parody)
spamming with a youtube link is the same thing as repeating a lie over and over...

it doesn't make it more true any more than repeating the assertion that you are a Toyota because you have a couple tires in your yard would be true

it's called argument from stupidity
because the idiots are too stupid to ever ask "Is there a model for that?"
but we already know there is a model for that... it is included in the THEORY of Evolution, which is based upon validated scientific evidence

this is where your "model" differs

your model cannot possibly supplant the theory of evolution because adaptation is already included in the theory
JVK
3 / 5 (8) Nov 09, 2015
spamming with a youtube link is the same thing as repeating a lie over and over...


That's why I have also included a link to the most recent published work from Dr Z's lab elsewhere. Why don't you tell others how their published work is included in the THEORY of Evolution.

Structural diversity of supercoiled DNA http://www.nature...440.html

Why don't you tell others how the bacterial flagellum re-evolved in 4 days and place your explanation into the context of supercoiled DNA, which links atoms to ecosystems in all living genera?

See: "Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system" http://www.scienc...abstract

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