Epigenetic Regulation of tRNA Biology in Cancer
[eng] Transfer RNAs (tRNAs) are essential molecules that allow the translation of the genetic code into amino acids. Extensive research during the last 50 years have revealed that, despite their apparently simple structure and function, tRNAs are more than simple adaptors in protein synthesis –they...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/181944 |
| Acceso en línea: | https://hdl.handle.net/2445/181944 http://hdl.handle.net/10803/673026 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer Epigenètica Metilació ADN RNA Cancer Epigenetics Methylation DNA |
| Sumario: | [eng] Transfer RNAs (tRNAs) are essential molecules that allow the translation of the genetic code into amino acids. Extensive research during the last 50 years have revealed that, despite their apparently simple structure and function, tRNAs are more than simple adaptors in protein synthesis –they are of high importance in normal cell functions. Reinforcing this, tRNA levels are tightly regulated to match the codon usage patterns of a given cell type or cellular status to meet the cellular specific needs and adapt to stress. Moreover, tRNA nucleoside modifications are critical for their function at multiple levels, such as translation efficiency and fidelity, wobbling and fragmentation. The relevance of tRNA regulation in cell physiology is emphasized by the recent discovery that these molecules and their derived fragments are deregulated in cancer. Not only tRNA biology imbalance is associated to malignant transformation, but it also actively participates in it. These alterations occur at multiple levels of tRNA biology, such as expression, nucleoside modification and fragmentation, but many open questions remain unanswered. Cancer- specific tRNA deregulation is a very new and still unexplored discipline, and further studies are required to fully understand the molecular mechanisms that account for these alterations and their relevance in tumor biology. Because alterations in DNA methylation constitute a frequent mechanism by which transformed cells acquire their malignant characteristics, the cornerstone of this thesis is the description of epigenetic lesions that support the cancer-associated tRNA deregulation. To this end, we have designed and performed two independent studies to unveil the epigenetic regulation of tRNA biology in cancer. In the first study, we highlighted the tumor-specific epigenetic silencing of TYW2 as a mechanism to induce tRNAPhe hypomodification at position 37, a phenomenon that was observed for the first time more than forty years ago but whose cause and consequences have remained obscure. Our results established the connection between this epigenetic defect and a phenotype that enhances -1 ribosome frameshifting events to ultimately confer increased migratory capacities and mesenchymal features to the transformed colon cells. In the second study, we established a founded connection between cancer-associated DNA methylation defects with alterations in the expression of specific tRNAs. Our analyses also revealed that the oncogenic tRNA-Arg-TCT-4-1 overexpression in endometrial cancer was guided by DNA hypomethylation. Most importantly from the clinical perspective, the epigenetic alterations identified in both studies can anticipate the patients’ outcome, for which they may serve as biomarkers to allow the identification of high-risk patients that may benefit from a more comprehensive surveillance or complementary therapeutic strategies. |
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