Mehr als ACGT(U)?

Mehr als ACGT(U)?

21. Juli 2011

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, researchers have discovered the seventh and eighth bases of DNA.

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 genes that had been silenced by DNA methylation.

The research was funded by the Howard Hughes Medical Institute and the National Institutes of Health.

Study co-authors from UNC include Shinsuke Ito, Ph.D.; Li Shen, Ph.D.; Susan C. Wu, Ph.D.; Leonard B. Collins and James A. Swenberg, Ph.D.

4. Mai 2015

Is there a sixth DNA base? A team of researchers suggests that the methyl-adenine that would regulate the expression of certain genes in eukaryotic cells could have a specific role in stem cells and in early stages of development.

DNA (deoxyribonucleic acid) is the main component of our genetic material. It is formed by combining four parts: A, C, G and T (adenine, cytosine, guanine and thymine), called bases of DNA combine in thousands of possible sequences to provide the genetic variability that enables the wealth of aspects and functions of living beings.

Two more bases: the Methyl-cytosine and Methyl-adenine

In the early 80s, to these four „classic“ bases of DNA was added a fifth: the methyl-cytosine (mC) derived from cytosine. And it was in the late 90’s when mC was recognized as the main cause of epigenetic mechanisms: it is able to switch genes on or off depending on the physiological needs of each tissue.

In recent years, interest in this fifth DNA base has increased by showing that alterations in the methyl-cytosine contribute to the development of many human diseases, including cancer.

Today, an article published in Cell by Manel Esteller, director of the Epigenetics and Cancer Biology Program of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona, describes the possible existence of a sixth DNA base, the methyl-adenine (mA), which also help determine the epigenome and would therefore be key in the life of the cells.

In bacteria and in complex organisms

„It was known for years that bacteria, evolutionarily very distant living organisms of us, had mA in its genome with a protective function against the insertion of genetic material from other organisms. But it was believed that this was a phenomenon of primitive cells and it was very static“ describes Manel Esteller.

„However, this issue of Cell publishes three papers suggesting that more complex cells called eukaryotes such as the human body cells, also present the sixth DNA base. These studies suggest that algae, worms and flies possess mA and it acts to regulate the expression of certain genes, thus constituting a new epigenetic mark. This work has been possible thanks to the development of analytical methods with high sensitivity because levels of mA in described genomes are low. In addition it seems that mA would play a specific role in stem cells and early stages of development, „explains the researcher.

„Now the challenge we face is to confirm this data and find out whether mammals, including humans, we also have this sixth DNA base, and consider what its role is.“

24. Juni 2015

Adenine, guanine, cytosine, and thymine. How these four DNA bases are ordered determines the makeup of a genome. And now, researchers have discovered an extra DNA base, called 5-Formylcytosine, or 5fC. They’re not sure what it does just yet, but it’s stable in every living tissue in the bodies of mice. The findings were published in Nature Chemical Biology this week.

In addition to the familiar A, G, C, and T, there are also many small chemical modifications to DNA that affect how sequences are interpreted. These are known as epigenetic marks, and they can control when certain genes are switched on or off. For example, when methyl groups – a chemical tag with one carbon and two hydrogen atoms – were added to a particular gene in ants, researchers doubled their size. In humans, babies born to mothers who smoke show epigenetic changes that aren’t seen in the babies of nonsmokers.

First discovered in 2011, 5fC is one of these marks. It’s formed when enzymes add oxygen to methylated DNA, specifically DNA with methyl attached to cytosine. But at the time, researchers thought that 5fC was just a transitional state of cytosine, which was being removed by repair enzymes. As it turns out, 5fC isn’t temporary: It’s stable in living tissue, which means that it likely plays an important role.

A team led by University of Cambridge’s Shankar Balasubramanian used high-resolution mass spectrometry to examine the levels of 5fC in living adult and embryonic mouse tissues, as well as in mouse embryonic stem cells. 5fC, they discovered, is present in all tissues, though it was difficult to detect.

“This modification to DNA is found in very specific positions in the genome – the places which regulate genes,” first author Martin Bachman of Cambridge says in a statement. “In addition, it’s been found in every tissue in the body – albeit in very low levels.” Balasubramanian adds: “If 5fC is present in the DNA of all tissues, it is probably there for a reason.” It’s the most common in the brain, but even there, 5fC is present at 10 parts per million or less; elsewhere, that number drops to between 1 and 5 parts per million.

The team measured the uptake of stable carbon and hydrogen isotopes to 5fC in the DNA of mouse cells. If 5fC were a transient molecule, the isotope uptake would be high. But instead, they saw a lack of uptake in the adult brain tissue, suggesting that 5fC is, in fact, a stable modification. “It had been thought this modification was solely a short-lived intermediate,” Balasubramanian says, “but the fact that we’ve demonstrated it can be stable in living tissue shows that it could regulate gene expression and potentially signal other events in cells.”

While its function is a mystery for now, the team thinks that 5fC may alter the way that DNA is recognized by proteins, which could result in changes to the way genes are expressed.

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