What is it about?

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. Our article in the Proceedings of the National Academy of Sciences (PNAS) 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.

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Why is it important?

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. We 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". The Epigenetic blockade of the 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.

Perspectives

When we studied patients with colon cancer in early stages, the epigenetic defect of TYW2 and the loss of the nucleotide "Y" was associated with those tumors that, although small in size, already lead to less survival of the person. We would like to explore now how to restore the activity of the TYW2 gene and restore the longed-for “Y” piece in cancer in order to close the cycle of this story that began so brilliantly in 1975, at the dawn of modern molecular biology.

Manel Esteller
Josep Carreras Leukaemia Research Institute (IJC)

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This page is a summary of: Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer, Proceedings of the National Academy of Sciences, August 2020, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2003358117.
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