The double helix is not the only form of DNA: an Australian team identifies a quadruple structure in living human cells.

The genetic 'cut and paste' that does not alter the DNA

On April 25, 1953, almost 65 years ago, the journal Nature published a short article that, however, contained a revolution: the molecular structure of DNA, "the secret of life", as it was called by Watson and Crick.

The double helix that contains the genetic instructions of all living organisms became, from then on, an easily recognizable icon. However, this helical structure is not the only way for the genes to store their information. As if it were origami, DNA is able to fold and structure in other ways.

An Australian team has just identified a new four-fold structure whose existence had been observed 'in vitro' but had never before been demonstrated in the nucleus of living cells. The structure, called i-motif, consists of four strands of DNA whose strands are paired in a peculiar way.

If in the double helix that we all know, the nitrogenous bases are grouped in the form of base pairs C-G (cytosine and guanine) and A-T (adenine and thymine); in the new quadruple form identified in vivo, are the cytosines (C) the bases that form pairs between them (for this, one of them must be protonated). "This research reminds us that there are completely different DNA structures and that this could be key for our cells," said Daniel Christ, a professor at the Garvan Medical Research Institute and one of the main signatories of the work published this week. Nature Chemistry.

In order to detect the new structure, the researchers used a fragment of an antibody capable of recognizing and adhering specifically to the i-motif forms, disregarding any other DNA structure (other triple and quad forms have been previously identified). Thanks to fluorescence techniques, scientists could not only identify the structures in the nucleus of numerous human cells, but also contemplate their location.

"There was a debate about whether this structure could exist in the biological environment, it had been observed and studied 'in vitro', but some researchers suggested that it was only a laboratory curiosity, without biological functions. , which opens a new line of research, "says Raimundo Gargallo, professor at the Department of Chemical Engineering and Analytical Chemistry at the University of Barcelona. "65 years after its discovery, many suspect that the DNA structure still kept many secrets, this work confirms it", agrees Carlos González, head of the Dissolved Nucleic Acids Structure Group of the Rocasolano Chemical Physics Institute (CSIC).

Among other applications, they add, knowing the real existence of these structures supposes "being able to investigate new therapeutic targets". In fact, that path is already being explored with the G-quadruplex, also structures of four DNA strands whose existence in vivo was discovered about five years ago.

As in the case in this case, if the indications observed by the researchers are verified, the i-motif could also play a very important role in genomic regulation.

According to the data of the work, the i-motifs are present in some regions that are related to genetic regulation; that is, with the part of the DNA that works as a switch and causes some genes to 'turn on' or 'turn off' and, therefore, certain molecular mechanisms are set in motion. The simple deregulation of these mechanisms tends to have catastrophic consequences (for example, cancer), González explains.

On the other hand, scientists have also observed that i-motifs are not durable, but are transient structures that seem to break into a specific moment of cell life - mainly in a phase characterized by great activity of transcription and cell growth - to then disappear. They have also corroborated that they are more frequent in telomeres, the structures that cover the chromosomes and are intimately involved in the aging process.

Much remains to be investigated, says Gargallo, but the fact of having confirmed the existence in vivo of these structures is already good news because it opens the possibility of studying "a new therapeutic objective that could allow the control of genetic expression and , therefore, control diseases related to it, such as certain cancers.

The double helix is the predominant structure, the most common way that DNA has to store its information, but there are other patterns whose role is still not known in depth and may be very important for medicine, the researchers conclude.