The Other Face of an Editor: ADAR1 Functions in Editing‐Independent Ways

Licht, Konstantin; Jantsch, Michael F.

doi:10.1002/bies.201700129

Cited by 20 publications

(20 citation statements)

References 42 publications

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“…ADAR1, in particular, appears to impact the transcriptome via a number of mechanisms. As a result of interactions with other RNA bindings proteins ADAR1 has been shown to alter RNA stability 28 , RNA splicing 29 , miRNA processing 30 , and RNA storage 31 . In each case, these impacts were shown to be independent of ADAR1′s RNA editing capacity but generally involved direct RNA binding by ADAR1 suggesting AD-domain containing proteins generally function by regulating cellular RNAs.…”

Section: Two Adad1 Alleles Have Moderately Different Impacts On Male mentioning

confidence: 99%

ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility

Snyder

Chukrallah

Seltzer

et al. 2020

Sci Rep

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Adenosine-to-inosine RNA editing, a fundamental RNA modification, is regulated by adenosine deaminase (AD) domain containing proteins. Within the testis, RNA editing is catalyzed by ADARB1 and is regulated in a cell-type dependent manner. This study examined the role of two testis-specific AD domain proteins, ADAD1 and ADAD2, on testis RNA editing and male germ cell differentiation. ADAD1, previously shown to localize to round spermatids, and ADAD2 had distinct localization patterns with ADAD2 expressed predominantly in mid-to late-pachytene spermatocytes suggesting a role for both in meiotic and post-meiotic germ cell RNA editing. AD domain analysis showed the AD domain of both ADADs was likely catalytically inactive, similar to known negative regulators of RNA editing. To assess the impact of Adad mutation on male germ cell RNA editing, CRISPRinduced alleles of each were generated in mouse. Mutation of either Adad resulted in complete male sterility with Adad1 mutants displaying severe teratospermia and Adad2 mutant germ cells unable to progress beyond round spermatid. However, mutation of neither Adad1 nor Adad2 impacted RNA editing efficiency or site selection. Taken together, these results demonstrate ADAD1 and ADAD2 are essential regulators of male germ cell differentiation with molecular functions unrelated to A-to-I RNA editing. RNA editing is a class of post-transcriptional modification that enhances the complexity of the transcriptome 1. On a molecular level, RNA editing is the irreversible chemical modification of a nucleotide within an intact RNA. Two basic types of RNA editing are observed in mammals, adenosine to inosine and cytosine to uridine, of which adenosine to inosine (A-to-I) occurs much more frequently 2. A-to-I RNA editing may occur at one or more sites in a given target RNA and across the entire population of a target RNA or a fraction thereof. To date, A-to-I RNA editing has been observed in a diverse range of RNAs including mRNAs, small RNAs, and long noncoding RNAs 3,4. Functionally, inosine mimics the behavior of guanine and is read as such by the translational machinery 5 , thus A-to-I RNA editing events behave as A-to-G mutations on the RNA level. As a consequence, the outcome of A-to-I RNA editing varies widely based on the RNA target and the edited site or sites within the target. Reported impacts of RNA editing include altered protein coding potential 6 , splicing patterns 7 , and microRNA recognition (either from edits within miRNAs 8 themselves or their targets 2). The physiological relevance of RNA editing is clear as animals deficient for A-to-I RNA editing enzymes often show severe physiological defects 9-11. In mammals, RNA editing is catalyzed by two adenosine deaminase (AD) domain-containing proteins: Adenosine Deaminase, RNA-specific 1 and 2 (ADAR1 and ADAR2 in the human, and ADAR and ADARB1 in the mouse, respectively). Both enzymes contain at least one double-stranded RNA binding motif and an AD domain, which directly catalyzes the conversion of adenosine to inosine 5. ...

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Section: Two Adad1 Alleles Have Moderately Different Impacts On Male mentioning

confidence: 99%

ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility

Snyder

Chukrallah

Seltzer

et al. 2020

Sci Rep

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show abstract

“…The divergence in survival between rescued ADAR1-null and editing-deficient mice, however, may indicate editing-independent functions of ADAR1, especially in early post-natal development. Indeed, several groups have described potential ADAR1 editing-independent MDA5-independent functions of ADAR1 [ 45 , 77 , 78 ]. As yet, however, it is not clear why the knockout alleles have reduced survival compared with the editing-deficient mice when MDA5 or MAVS are co-deleted.…”

Section: The Application Of Genetics To Understand the In Vmentioning

confidence: 99%

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

Heraud-Farlow

Walkley

2020

Open Biol.

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Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo . Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.

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“…Similarly, only edited Gria2 pre-mRNA is spliced efficiently, and unedited pre-mRNA is retained in the nucleus [18,47,48] (Figure 1D). Moreover, ADAR proteins can interfere with pre-mRNA processing independently of A-to-I editing [50]. For instance, ADAR1 can compete with 3 0 -UTR processing factors and thereby influence transcript length [51].…”

Section: Interplay Of A-to-i Editing and Mrna Processingmentioning

confidence: 99%

The Editor’s I on Disease Development

2019

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Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering the coding, folding, splicing, or transport of transcripts. A-to-I editing is tightly regulated. Altered editing has severe consequences for human health and can cause interferonopathies, neurological disorders, and cardiovascular disease, as well as impacting on cancer progression. ADAR1-mediated RNA editing plays an important role in antiviral immunity and is essential for distinguishing between endogenous and viral RNA, thereby preventing autoimmune disorders. Interestingly, A-to-I editing can be used not only to correct genomic mutations at the RNA level but also to modulate tumor antigenicity with large therapeutic potential. We highlight recent developments in the field, focusing on cancer and other human diseases. A-to-I Editing and ADAR EnzymesHigh-throughput sequencing and mass spectrometry have identified massive and diverse RNA modifications which have bolstered the idea that gene expression can be regulated at the transcript level [1,2]. A-to-I editing (see Glossary) is a prevalent type of RNA modification during which adenosines in double-stranded (ds) or structured RNAs are deaminated, leading to nucleotide differences between RNA and DNA. Inosine is primarily interpreted as guanosine by the cellular machinery but can also be decoded as adenosine or uridine [3,4]. Hence, adenosine deamination can affect coding potential and translation efficiency, change splice sites,or mask endogenous RNAs from the innate immune system [1,4]. In humans, editing occurs at millions of sites, mostly in noncoding parts of the transcriptome such as introns and untranslated regions (UTRs) [5][6][7]. By contrast, editing in protein-coding regions of transcripts is relatively rare, and only about 40 such sites are conserved in mammals [8].A-to-I editing is catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes which require dsRNA for binding and editing. Two catalytically active ADARs (ADAR1 and ADAR2) are expressed in mammals. ADAR3 is a third member of the family but is catalytically inactive [9]. ADAR1 is expressed in two isoforms. A shorter isoform (ADAR1-p110) is expressed from a constitutively active promoter, whereas a longer isoform (ADAR1-p150) is interferon (IFN)-inducible [10]. Mice lacking ADAR1 die at embryonic (E) day 12.5 accompanied by an elevated IFN response [11][12][13]. Lethality can be rescued when cytoplasmic sensors of (viral) dsRNAs are also deleted, suggesting that inosines help to discriminate 'self' from 'non-self' dsRNA [14][15][16]. Adar2 knockout mice die within 3 weeks after birth [17]. This phenotype can be rescued when a pre-edited allele of the glutamate receptor Gria2 gene is coexpressed, demonstrating that ADAR2-mediated editing of Gria2 is essential [18].We review the role of A-to-I editing in disease, including its impact on cancer progression and innate immunity. We also discuss recent advances in s...

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The Other Face of an Editor: ADAR1 Functions in Editing‐Independent Ways

Cited by 20 publications

References 42 publications

ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility

ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

The Editor’s I on Disease Development

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