RESUMEN
In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements. Therefore, the impact of the hypo- or hyper-editing found in specific cancers remains unknown. Moreover, it is yet unclear whether or not changes in RNA editing and ADAR expression levels facilitate or even drive cancer progression or are just a byproduct of other affected pathways. In both cases, however, the levels of RNA editing and ADAR enzymes can possibly be used as specific biomarkers, as their levels change differently in specific malignancies. More significantly, recent studies suggest that ADAR enzymes can be used to reverse the oncogenic process, suggesting a potential for gene therapies. This review focuses on new findings that suggest that RNA editing by ADARs can affect cancer progression and even formation. We also discuss new possibilities of using ADAR enzymes and RNA editing as cancer biomarkers, indicators of chemotherapeutic drug sensitivity, and even to be themselves potential therapeutic tools.
Asunto(s)
Adenosina Desaminasa/genética , Carcinogénesis/genética , Neoplasias/genética , Edición de ARN/genética , Proteínas de Unión al ARN/genética , Adenosina/genética , Adenosina/metabolismo , Adenosina Desaminasa/metabolismo , Elementos Alu/genética , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/patología , Terapia Genética/métodos , Humanos , Inosina/genética , Inosina/metabolismo , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Neoplasias/patología , Neoplasias/terapia , Oncogenes/genética , Edición de ARN/efectos de los fármacos , ARN Bicatenario/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
A-to-I RNA editing, catalyzed by ADAR proteins, is widespread in eukaryotic transcriptomes. Studies showed that, in C. elegans, ADR-2 can actively deaminate dsRNA, whereas ADR-1 cannot. Therefore, we set out to study the effect of each of the ADAR genes on the RNA editing process. We performed comprehensive phenotypic, transcriptomics, proteomics, and RNA binding screens on worms mutated in a single ADAR gene. We found that ADR-1 mutants exhibit more-severe phenotypes than ADR-2, and some of them are a result of non-editing functions of ADR-1. We also show that ADR-1 significantly binds edited genes and regulates mRNA expression, whereas the effect on protein levels is minor. In addition, ADR-1 primarily promotes editing by ADR-2 at the L4 stage of development. Our results suggest that ADR-1 has a significant role in the RNA editing process and in altering editing levels that affect RNA expression; loss of ADR-1 results in severe phenotypes.