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The role of the forgotten

Stretches of RNA previously looked on as useless regulate the production of proteins linked to cancer

Like the scavengers who rummage for valuable objects in the midst of the leftovers of society, some molecular biologists are extracting precious information from apparently less noble stretches of human genetic material. In an article shortly to be published in the British magazine Oncogene, a group of Brazilian researchers shows that fragments usually disdained from a specific class of RNA – the molecule of ribonucleic acid, derived from the famous DNA and of fundamental importance for the production of proteins – are not useless. Contrary to what the genetics textbooks still postulate, pieces of intronic antisense RNA are important for cell biology. More than this: their greater or lesser presence in an organism may be related to the stage of development of complex diseases and perhaps work as a marker for the degree of malignity of certain forms of cancer.

This hypothesis gained strength after the scientists compared about 4,000 segments of three distinct classes of RNA in healthy and tumorous prostate tissue, removed from 27 patients. This task was done with the help of a device called a DNA microarray, built at the Chemistry Institute of the University of São Paulo (IQ-USP). At the end of the work, 12 pieces of RNA revealed themselves as being very relevant for determining the level of aggressiveness of the tumor ? six of them were stretches from the hitherto disdained intronic antisense RNA.

“We showed that the messages issued by this kind of RNA participate in the process of regulating the production of proteins linked to the development of cancer prostate”, explains Sergio Verjovski-Almeida, from IQ-USP, the leader of the team that drafted the article on the discovery for Oncogene. “They cannot be ignored any more in studies about gene expression in diseases and should be incorporated into the arsenal of tools for cancer research.” Researchers from the National Cancer Institute (Inca), in Rio de Janeiro, and from the Syrio-Lebanese and Albert Einstein hospitals, from São Paulo, also took part in the work.

A pinch of genomics helps one to understand what these intronic antisense RNA fragments are. A gene is an ordered sequence of chemical bases – adenine (A) cytosine (C), guanine (G) and thymine (T) – located in one of the strands of the DNA molecule. The strand where the gene is called sense, and the other, which is complementary to it, is called antisense. The bases form two kinds of regions in the inside of a gene: the exons and the introns.

The regions with exons provide the recipe that commands the production of a protein in the cells. Between one exon and another, the introns appear, which are longer segments that do not have any apparent function. Until recently, a region with an intron was looked on as “dirt” in the middle of a gene, without a biological function. There are two kinds of intronic regions: those located in the sense strand of the DNA, inside the gene, and those to be found in the antisense strand (please see the illustration).

What do RNA and cancer have to do with this? Here comes the explanation. When it is expressed (activated) in a human tissue, healthy or with some disease, like cancer, a gene generates pieces of several classes of messenger RNA. These fragments of RNA are called transcripts by molecular biologists. The stretches of RNA that originate the exons make up the formula of the protein.

The transcripts originating from the introns (sense and antisense) do not come into the recipe and, until recently, were looked on as genomic junk. “Scientific literature had already shown that intronic sense RNA took part in regulating the synthesis of proteins”, says biologist Eduardo M. Reis, another author of the Brazilian study. “Our contribution was to reveal that there are intronic RNAs, derived exclusively from the antisense strand, which also act in this process.” In the case of prostate cancer, one of these intronic RNAs (both sense and antisense), RASSF1, worked like a marker of the aggressiveness of the tumors. The patients with cancer at an advanced stage showed low levels of this kind of RNA.