They discover one of the causes of resistance in liver cancer

For cells, error correction mechanisms are very important, because in the complex cellular activity there are constant malfunctions. But when it comes to killing cancer cells, what matters is precisely causing errors. Radiation therapy and chemotherapy cause them by breaking the DNA of cells. However, there are tumor cells that have exceptionally efficient DNA repair machinery, and this allows them to escape such cancer treatments.

Puri Fortes’s team, from the Center for Applied Medical Research (CIMA) at the University of Navarra, in Spain, discovered a few years ago that approximately half of patients with hepatocellular carcinoma (the most common liver cancer) produce a molecule of RNA, called NIHCOLE, which is found above all in the most aggressive tumors and is associated with a poor prognosis. Fortes, Óscar Llorca, from the National Cancer Research Center (CNIO) in Spain, and Fernando Moreno-Herrero, a researcher at Spain’s Higher Council for Scientific Research (CSIC) at the Spanish National Center for Biotechnology (CNB), concluded that NIHCOLE helps to very effectively repair broken DNA and, therefore, radiotherapy is less effective in those tumors in which it is present. By removing NIHCOLE, cancer cells treated with radiation therapy die more easily.

But the researchers did not know the molecular mechanism by which NIHCOLE facilitates the repair of DNA breaks. Now, in a new investigation, the riddle has been solved. NIHCOLE forms a bridge that joins the broken DNA fragments. “NIHCOLE interacts simultaneously with proteins that recognize the two ends of a fragmented DNA, as if it stapled them together”, explain Llorca and Moreno-Herrero. “The use of NIHCOLE inhibitor drugs may represent a novel therapy for the most common liver cancer,” these researchers indicate.

Artist’s impression of a cancer cell. (Illustration: Amazings/NCYT)

To understand how NIHCOLE works, Moreno-Herrero’s group has used magnetic tweezers, a nanotechnology technique that makes it possible to study the physical characteristics of molecules separately. The researchers have designed a DNA molecule that mimics a broken DNA and that makes it possible to detect the union between the two fragmented ends. First, they glue a tiny magnetic ball to one of the ends of the DNA, only thousandths of a millimeter; then, with magnetic tweezers, they pull on that end. The length of the stretched DNA indicates whether it is reconstituted DNA, in which the broken ends of the DNA have stuck together, or whether, on the contrary, there is still a fracture.

For the authors of the work, these data show that NIHCOLE “confers benefits to tumor cells by helping them repair DNA breaks, sustaining the malignant proliferation of cancer cells despite the accumulation of DNA damage resulting from stress.” produced by cell division itself.

NIHCOLE is not a protein synthesized by a gene, but an RNA molecule. It is part of what is produced from what biologists called “junk DNA” two decades ago, when the human genome was sequenced. They mistakenly believed that this DNA was useless. Llorca explains it: “One of the central dogmas of biology is that the information contained in each gene, in DNA, is translated into proteins. So scientists were stunned when they discovered that only 2% of our DNA contained genes; what was the rest of our genome for? It is unthinkable that 98% of the genome is junk or useless DNA. In the last decade it has been shown that part of this obscure genome produces very long RNA molecules, some with a prevalent function in cancer”.

NIHCOLE is one of these long RNA molecules, the existence and functions of which have been known for so little that they still amaze biologists. It is also surprising that a small piece of NIHCOLE is enough to exert the effect of a molecular staple.

“This would make it possible to develop drugs that block or distort this structure, and thus improve the efficacy of radiotherapy or chemotherapy in cancer patients”, state the authors of the paper.

The study is titled “APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining”. And it has been published in the academic journal Cell Reports. (Source: CNIO / CSIC)