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The origin of the ADAR gene family and animal RNA editing.

ABSTRACT: BACKGROUND: ADAR (adenosine deaminase acting on RNA) proteins convert adenosine into inosine in double-stranded RNAs and have been shown to increase gene product diversity in a number of bilaterians, particularly mammals and flies. This enzyme family appears to have evolved from an ADAT (adenosine deaminase acting on tRNA) ancestor, via the addition of a double-stranded RNA binding domain. The modern vertebrate ADAR family is comprised of ADAD, ADAR2 and ADAR1, each of which has a conserved domain architecture. To reconstruct the origin of this protein family, we identified and categorised ADAR family members encoded in the genomes and/or transcriptomes of early-branching metazoan and closely related non-metazoan taxa, including thirteen sponge and ten ctenophore species. RESULTS: We demonstrate that the ADAR protein family is a metazoan innovation, with the three ADAR subtypes being present in representatives of the earliest phyletic lineages of animals - sponges and ctenophores - but not in other closely related choanoflagellate and filasterean holozoans. ADAR1 is missing from all ctenophore genomes and transcriptomes surveyed. Depending on the relationship of sponges and ctenophores to the rest of the Metazoa, this is consistent with either ADAR1 being lost in ctenophores, as it has been in multiple metazoan lineages, or being an innovation that evolved after ctenophores diverged from the rest of the animal kingdom. The presence of Z-DNA binding domains in some sponge ADARs indicates an ancestral ADAR included this domain and it has been lost in multiple animal lineages. CONCLUSIONS: The ADAR family appears to be a metazoan innovation, with all family members in place in the earliest phyletic branches of the crown Metazoa. The presence of ADARs in sponges and ctenophores is consistent with A-to-I editing being a post-transcriptional regulatory mechanism that was used by the last common ancestor to all living animals and subsequently has been preserved in most modern lineages.

SUBMITTER: Grice LF

PROVIDER: S-EPMC4323055 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The origin of the ADAR gene family and animal RNA editing.

Grice Laura F LF Degnan Bernard M BM

BMC evolutionary biology 20150129

<h4>Background</h4>ADAR (adenosine deaminase acting on RNA) proteins convert adenosine into inosine in double-stranded RNAs and have been shown to increase gene product diversity in a number of bilaterians, particularly mammals and flies. This enzyme family appears to have evolved from an ADAT (adenosine deaminase acting on tRNA) ancestor, via the addition of a double-stranded RNA binding domain. The modern vertebrate ADAR family is comprised of ADAD, ADAR2 and ADAR1, each of which has a conserv ...[more]

PMID: 25630791

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Project description:RNA editing by RNA specific adenosine deaminase acting on RNA (ADAR) is increasingly being found to alter microRNA (miRNA) regulation. Editing of miRNA transcripts can affect their processing, as well as which messenger RNAs (mRNAs) they target. Further, editing of target mRNAs can also affect their complementarity to miRNAs. Notably, ADAR editing is often increased in malignancy with the effect of these RNA changes being largely unclear. In addition, numerous reports have now identified an array of miRNAs that directly contribute to various malignancies although the majority of their targets remain largely undefined. Here we propose that modulating the targets of miRNAs via mRNA editing is a frequent occurrence in cancer and an underappreciated participant in pathology. In order to more accurately characterize the relationship between these two regulatory processes, this study examined RNA editing events within mRNA sequences of two breast cancer cell lines (MCF-7 and MDA-MB-231) and determined whether or not these edits could modulate miRNA associations. Computational analyses of RNA-Seq data from these two cell lines identified over 50,000 recurrent editing sites within human mRNAs, and many of these were located in 3' untranslated regions (UTRs). When these locations were screened against the list of currently-annotated miRNAs we discovered that editing caused a subset (~9%) to have significant alterations to mRNA complementarity. One miRNA in particular, miR-140-3p, is known to be misexpressed in many breast cancers, and we found that mRNA editing allowed this miRNA to directly target the apoptosis inducing gene DFFA in MCF-7, but not in MDA-MB-231 cells. As these two cell lines are known to have distinct characteristics in terms of morphology, invasiveness and physiological responses, we hypothesized that the differential RNA editing of DFFA in these two cell lines could contribute to their phenotypic differences. Indeed, we confirmed through western blotting that inhibiting miR-140-3p increases expression of the DFFA protein product in MCF-7, but not MDA-MB-231, and further that inhibition of miR-140-3p also increases cellular growth in MCF-7, but not MDA-MB-231. Broadly, these results suggest that the creation of miRNA targets may be an underappreciated function of ADAR and may help further elucidate the role of RNA editing in tumor pathogenicity.

Dataset Information

The origin of the ADAR gene family and animal RNA editing.

Publications

The origin of the ADAR gene family and animal RNA editing.

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