Scientists identify seventh and eighth bases of DNA

July 21, 2011, University of North Carolina

For decades, scientists have known that DNA consists of four basic units -- adenine, guanine, thymine and cytosine. Those four bases have been taught in science textbooks and have formed the basis of the growing knowledge regarding how genes code for life. Yet in recent history, scientists have expanded that list from four to six.

Now, with a finding published online in the July 21, 2011, issue of the journal Science, researchers from the UNC School of Medicine have discovered the seventh and eighth bases of DNA.

These last two bases – called 5-formylcytosine and 5 carboxylcytosine – are actually versions of cytosine that have been modified by Tet proteins, molecular entities thought to play a role in DNA demethylation and stem cell reprogramming.

Thus, the discovery could advance stem cell research by giving a glimpse into the DNA changes – such as the removal of chemical groups through demethylation – that could reprogram adult cells to make them act like stem cells.

"Before we can grasp the magnitude of this discovery, we have to figure out the function of these new bases," said senior study author Yi Zhang, Ph.D., Kenan Distinguished Professor of biochemistry and biophysics at UNC and an Investigator of the Howard Hughes Medical Institute. "Because these bases represent an intermediate state in the demethylation process, they could be important for cell fate reprogramming and cancer, both of which involve DNA demethylation."

Much is known about the "fifth base," 5-methylcytosine, which arises when a chemical tag or methyl group is tacked onto a cytosine. This methylation is associated with gene silencing, as it causes the DNA's double helix to fold even tighter upon itself.

Last year, Zhang's group reported that Tet proteins can convert 5 methylC (the fifth base) to 5 hydroxymethylC (the sixth base) in the first of a four step reaction leading back to bare-boned cytosine. But try as they might, the researchers could not continue the reaction on to the seventh and eighth bases, called 5 formylC and 5 carboxyC.

The problem, they eventually found, was not that Tet wasn't taking that second and third step, it was that their experimental assay wasn't sensitive enough to detect it. Once they realized the limitations of the assay, they redesigned it and were in fact able to detect the two newest bases of DNA. The researchers then examined embryonic stem cells as well as mouse organs and found that both bases can be detected in genomic DNA.

The finding could have important implications for stem cell research, as it could provide researchers with new tools to erase previous methylation patterns to reprogram adult cells.

It could also inform cancer research, as it could give scientists the opportunity to reactivate tumor suppressor that had been silenced by methylation.

Explore further: Tet further revealed: Studies track protein relevant to stem cells, cancer

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not rated yet Jul 21, 2011
I'm NOT retaking genetics thank you very much. hardest class ever! interesting article.
5 / 5 (1) Jul 21, 2011
I'm NOT retaking genetics thank you very much. hardest class ever! interesting article.

Yeah, was a weed-out class when I took it, people audibly saying "wtf?" (the non-acronym version) at tests, girls leaving from the final in tears.

Anyone know, do they still teach just 4 bases? Maybe just tack the methylations onto epigenetics as a cytosine asterisk?
4 / 5 (8) Jul 21, 2011
So called 'weed out' classes are or were called 'filter' classes at colleges. Designed as necessary classes for certain majors (they really were needed), they were made more difficult by schools in order to increase the failure rate hence the drop out rate for any given major. Calculus is one of those for engineering, so is statics and, of all things, 'engineering materials'. Tales of women 'dropping like flies' in calculus classes are legendary. Trouble is, I have seen this with my own eyes.
5 / 5 (1) Jul 21, 2011

Anyone know, do they still teach just 4 bases? Maybe just tack the methylations onto epigenetics as a cytosine asterisk?

I recently finished a genetics course. We learned about methylation, but we didn't discuss methylated cytosine as a "fifth" base. We still learned the 4 bases (5 if you count uracil). Of course this might vary between textbooks and professors.
5 / 5 (3) Jul 21, 2011
I'm thinking that the authors missed Inosine as one of the canonical bases, of which I want to believe there are seven. You've got ACGT, and they are clearly the most important because they are the information repository that form chromosomes. U (Uracil) replaces T when DNA is copied into RNA, just because nature wanted to fuck with 19 year old trying to do well in cell biology. Well, actually, Thymidine is more stable than Uracil, which probably came first when the genetic material of life consisted of enzymatic and information-holding molecules of RNA. While Thymidine is more stable, it does spontaneously dimerize when adjacent bases in DNA are irradiated with UV light, and animals have all kinds of biochemical solutions to the problem of being exposed to sunlight primarily because of Thymidine's reactivity. So, I imagine that Thymidine was a vast improvement over our previous state of affairs.

5 / 5 (1) Jul 21, 2011
But, that's only 5. The article mentions methyl-G, which is what our cells do to turn off the transcription of certain genes. I wouldn't actually count that as another base, since it's just a simple modification. But, if we are counting modifications after the polynucleotide chain has formed, then we clearly need to throw Inosine into the mix as well. Without Inosine we would be wanting for a convenient manner in which to get quadruple helices to hold the ends of our chromosomes together. That that is at least as important as mthyl-G gene imprinting, if you ask me.
So, my call is that there are either five bases or there are seven bases. The research has either brought the number to seven or to nine. But, it has clearly not brought the number to eight.
not rated yet Jul 21, 2011
Scientists identify seventh and eighth bases of DNA

This from a bunch of guys who probably never made it past third base!

(I'm sorry, I couldn't help myself.)

It actually sounds like they've done some good work here, although I have to question one set of definitions, which admittedly was probably not up to (or determined by) these researchers:

Because these bases represent an intermediate state in the demethylation process...

If these bases represent an intermediate state in the demethylation process, then shouldn't they probably not be referred to as "bases", even though (temporarily?) functioning as such? Because I was wondering...

Just clearly advertised my lack of knowledge on the subject, didn't I? Oh well... damage done...
not rated yet Jul 22, 2011
So if cytosine has four different methylations that can now be considered as new bases as well, surely there are similar groups for the other three? Or do adenine, guanine and thymine only EVER appear as adenine, guanine and thymine?
3.5 / 5 (2) Jul 22, 2011
Trouble is, I have seen this with my own eyes.

And a good thing, too. Would you have to explain someone years and years into their studies at university that they won't make it? Rather have one or to really tough courses at the beginning. Anyone who pases those will likely go on to graduate.

While people may be 'in tears' about such hard exams they will, later in life, realize that it saved them a lot time which would have been wasted otherwise.
1 / 5 (4) Jul 22, 2011
So in other words, they aren't new bases, but modofications of existing bases. I guess this amounts to scientific sectarianism where, like religion, you put a twist on something in a misleading way to claim it as your own.
4 / 5 (4) Jul 22, 2011
You mean like adding an oxygen atom to a hydrogen molecule and calling it 'water' is misleading and that such an action amounts to scientific sectarianism?

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