Our study has compiled evidence about determinants of QOL for children with cancer and childhood cancer survivors from the existing literature. Future research can build on this evidence base to expand the range of factors studied as most research to date has focused on medical and treatment factors.

ADAR RNA editing enzymes (denosine eminases acting on NA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on, which has a single gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems.

Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosineto-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I-like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer. The Epitranscriptome, ADARs, and InosinesModified bases act as marks of self-RNA to reduce innate immune responses to endogenous cellular RNA. Over 170 different types of enzymatic RNA modifications are known to occur in stable RNAs, such as tRNAs and rRNAs, where many contribute to their high stabilities and optimise the activities of these RNAs [1]. Different types of base modifications have also been found in eukaryotic mRNAs, where they are called epitranscriptomic (see Glossary) modifications [2]. Base modifications that have been detected in mRNA include adenosine to inosine (A-to-I) deamination and cytosine to uracil (C-to-U) deamination, N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), 5-methylcytosine (5mC), and pseudouridine (ψ), as well as ribose 2′O-methyl [1]. Many of these modifications affect innate immune responses to RNA [3-6], and understanding these effects has been critical for development of mRNA therapeutics and vaccines [7].We focus here on A-to-I deamination, which was one of the first RNA base modifications identified; it is abundant in tRNAs and plays a key role in tRNA wobble decoding. It was also one of the first epitranscriptomic mRNA modifications identified, because it is readily detected by RNA sequencing (RNA-seq). A-to-I RNA modification/editing found in mRNAs is catalysed by adenosine deaminases acting on RNAs (ADARs). In mammals, there are three ADAR family members: ADAR1 and ADAR2 deaminate double-stranded (ds)RNA, whereas ADAR3 is enzymatically inactive (for review, see [8]). This review focuses primarily on ADAR1, summarising the evidence for its role in innate immunity (Figure 1) and how this role of ADARs is evolutionarily conserved. We also aim to clarify how and when A-to-I conversion acts as an epitranscriptomic RNA modification versus the rarer cases where it acts as an RNA editing event. This RNA modification role of the ADARs has been, and will continue to be, a trailblazer for understanding epitranscriptomic roles of many types of RNA modifications. Finally, we also summarise human diseases and SNPs associated with ADAR1 and the roles of ADAR1 in tumour immunity. ADAR1, the Inosinome, and Effects on Three Levels ADAR1The three ADARs are composed of two or more dsRNA-binding domains (dsRBDs) followed ...