6th base found in eukaryotic DNA

We used to think DNA was a double-stranded polymer of four nitrogenous bases—adenine (A), cytosine (C), guanine (G), and thymine (T)—which combined in zillions of different sequences to make genes in all their normal and mutated forms.

Other nitrogenous bases are known to exist, with methyl groups appended to the bases, such as 5-methylcytosine and N4-methylcytosine. N6-methyladenine (m6A) has also been previously detected in bacterial DNA. It plays a role in controlling gene expression, according to the scientific field of study known as epigenetics. In 1980, Science published a paper, saying this:

In most higher organisms, DNA is modified after synthesis by the enzymatic conversion of many cytosine residues to 5-methylcytosine. For several years, control of gene activity by DNA methylation has been recognized as a logically attractive possibility, but experimental support has proved elusive. However, there is now reason to believe, from recent studies, that DNA methylation is a key element in the hierarchy of control mechanisms that govern vertebrate gene function and differentiation.

So they kept looking for 5-methylcytosine in mammalian DNA, using more and more sensitivity in their techniques and instruments. After all, controlling gene expression is important in several areas of medical research, including cancer.

Sure enough, they found some 5-methylcytosine, but the methylated adenine still was seen only in bacterial cells, whose evolutionary histories are very different from ours.

At least by 2006, the other methylated bases in mammalian DNA had escaped detection. Even with very sensitive detection methods, scientists just couldn’t find much, if any, N6-methyladenine in mammalian DNA.

Now in last week’s edition of the journal Cell, three isolated reports suggest m6A may have a role in regulating gene expression, even in cells that aren’t bacterial in origin, such as algae, worms, and flies.

DNA N6-methyladenine (m6A) protects against restriction enzymes in bacteria. However, isolated reports have suggested additional activities and its presence in other organisms, such as unicellular eukaryotes. New data now find that m6A may have a gene regulatory function in green alga, worm, and fly, suggesting m6A as a potential “epigenetic” mark.

Still no m6A in mammalian cells, but at least we’ve found it in the eukaryotic world.

“It was known for years that bacteria … had [m6A] 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,” said Manel Esteller, an author on one of those papers.

“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 [m6A] 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 [m6A] in described genomes are low. In addition it seems that [m6A] would play a specific role in stem cells and early stages of development.

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

[Editor’s note: We can’t be sure what the short form for N6-methyladenine is, because some publications write m6A, others 6mA, and still others just mA.]