Before the first oncogene mutations were discovered in human cancer in the early 1980s, the 1970s provided the first data suggesting alterations in the genetic material of tumors. In this context, the prestigious magazine “Nature” published in 1975 the existence of a specific alteration in the transformed cell: an RNA responsible for carrying an amino acid to build proteins (transfer RNA) was missing a piece, the enigmatic nucleotide “Y”. After that outstanding observation, the most absolute silence and ignorance has reigned for forty-five years on the causes and consequences of not having that correct base in that RNA. The article published in the Proceedings of the National Academy of Sciences (PNAS) by the group of Dr. Manel Esteller solves this mystery by describing that in cancer cells the protein that generates the nucleotide “Y” is epigenetically inactivated, causing small but highly aggressive tumors.
Since the original discovery in 1975, there has been much biochemical work to characterize the enzymes involved in the different steps that lead to the desired nucleotide “Y”, a hypermodified guanine, but without connecting this characterization with its defect in tumor biology. Dr Esteller’s work have built the bridge between these two worlds by demonstrating that the epigenetic silencing of the TYW2 gene is the cause of the loss of the elusive nucleotide “Y”. Epigenetic blockade TYW2 gene occurs mainly in colon, stomach and uterine cancer. And it has undesirable consequences for healthy cells: the postman (RNA) that sends the signal to produce the bricks of our body (proteins) begins to accumulate errors and the cell takes on a different appearance, far from the normal epithelium, which we call mesenchymal and which it is associated with the appearance of metastasis. In this regard, when we study patients with colon cancer in early stages, the epigenetic defect of TYW2 and the loss of the nucleotide “Y” is associated with those tumors that, although small in size, already lead to less survival of the person
Reference
Rosselló-Tortella M, Llinàs-Arias P, Sakaguchi Y, Miyauchi K, Davalos V, Setien F, Calleja-Cervantes ME, Piñeyro D, Martínez-Gómez J, Guil S, Joshi R, Villanueva A, Suzuki T, Esteller M 2020, ‘Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer‘, Proc Natl Acad Sci USA, 17, 34, 20785-20793.
The effect of losing the TYW2 gene and the “Y” nucleotide in colon cancer. In the image on the left, cells from the colon with normal levels of TYW2 and the “Y” piece. In the image on the right, when the loss of TYW2 and the nucleotide “Y” occurs, colon cancer cells begin to migrate uncontrollably.