45-Year Cancer Mystery Solved; Epigenetic Silencing of Key Enzyme Prevents Synthesis of “Y” Nucleotide in Phenylalanine tRNA Causes Certain Small, But Highly Aggressive Tumors

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, in 1975 Nature published an article describing the existence of a specific alteration in the transformed cell: a transfer RNA (tRNA) responsible for carrying the amino acid phenylalanine to build proteins was missing a piece, the enigmatic nucleotide "Y” a hypermodulated guanine (https://pubmed.ncbi.nlm.nih.gov/163007/). After that seminal observation, silence and ignorance have reigned for forty-five years on the causes and consequences of not having that correct base in that tRNA. In an article that was just published online on August 10, 2020 in PNAS by the group of Manel Esteller (photo) (https://www.carrerasresearch.org/esteller-manel_124337), MD, PhD, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Professor of Genetics at the University of Barcelona in Spain, this 45-year-old mystery appears to have been solved by results showing that in certain cancer cells the enzyme (tRNA wybutosine-synthesizing protein 2) that generates the nucleotide "Y" is epigenetically inactivated, causing small, but highly aggressive tumors. The open-access PNAS article is titled "Epigenetic Loss of the Transfer RNA-Modifying Enzyme TYW2 Induces Ribosome Frameshifts in Colon Cancer." “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.
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