RNA editing activity is associated with splicing factors in lnRNP particles: The nuclear pre-mRNA processing machinery

Raitskin, Oleg; Cho, Dan‐Sung C.; Sperling, Joseph; Nishikura, Kazuko; Sperling, Ruth

doi:10.1073/pnas.111153798

Cited by 83 publications

(74 citation statements)

References 42 publications

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“…Editing and splicing may be coordinated events in mamma- lian cells, with pre-mRNAs exposed to ADARs at the time of their processing (Raitskin et al 2001;Bratt and Ohman 2003). Although we do not find evidence that editing has directly altered splice sites, base modifications of Alu duplexes could change local RNA structures and hinder the normal splicing process.…”

Section: Characterization Of Edited Transcriptscontrasting

confidence: 41%

Widespread RNA Editing of Embedded Alu Elements in the Human Transcriptome

Kim

Kim²,

Walsh³

et al. 2004

Genome Res.

484

448

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More than one million copies of the ∼300-bp Alu element are interspersed throughout the human genome, with up to 75% of all known genes having Alu insertions within their introns and/or UTRs. Transcribed Alu sequences can alter splicing patterns by generating new exons, but other impacts of intragenic Alu elements on their host RNA are largely unexplored. Recently, repeat elements present in the introns or 3′-UTRs of 15 human brain RNAs have been shown to be targets for multiple adenosine to inosine (A-to-I) editing. Using a statistical approach, we find that editing of transcripts with embedded Alu sequences is a global phenomenon in the human transcriptome, observed in 2674 (∼2%) of all publicly available full-length human cDNAs (n = 128,406), from >250 libraries and >30 tissue sources. In the vast majority of edited RNAs, A-to-I substitutions are clustered within transcribed sense or antisense Alu sequences. Edited bases are primarily associated with retained introns, extended UTRs, or with transcripts that have no corresponding known gene. Therefore, Alu-associated RNA editing may be a mechanism for marking nonstandard transcripts, not destined for translation

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Section: Characterization Of Edited Transcriptscontrasting

confidence: 41%

Widespread RNA Editing of Embedded Alu Elements in the Human Transcriptome

Kim

Kim²,

Walsh³

et al. 2004

Genome Res.

484

448

View full text Add to dashboard Cite

show abstract

“…Western Immunoblot Analysis-Western blot analysis was done using mAb 15.8.6 and the Renaissance® chemiluminescence detection system (PerkinElmer Life Sciences) as described (38). Blots were double immunostained with anti-␤-tubulin mAb T-5293 (Sigma) for normalization of the ADAR1 expression levels.…”

Section: Methodsmentioning

confidence: 99%

Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene

Wang

Miyakoda

Yang

et al. 2004

Journal of Biological Chemistry

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435

470

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One type of RNA editing involves the conversion of adenosine residues into inosine in double-stranded RNA through the action of adenosine deaminases acting on RNA (ADAR). A-to-I RNA editing of the coding sequence could result in synthesis of proteins not directly encoded in the genome. ADAR edits also non-coding sequences of target RNAs, such as introns and 3 -untranslated regions, which may affect splicing, translation, and mRNA stability. Three mammalian ADAR gene family members (ADAR1-3) have been identified. Here we investigated phenotypes of mice homozygous for ADAR1 null mutation. Although live ADAR1 ؊/؊ embryos with normal gross appearance could be recovered up to E11.5, widespread apoptosis was detected in many tissues. Fibroblasts derived from ADAR1 ؊/؊ embryos were also prone to apoptosis induced by serum deprivation. Our results demonstrate an essential requirement for ADAR1 in embryogenesis and suggest that it functions to promote survival of numerous tissues by editing one or more double-stranded RNAs required for protection against stress-induced apoptosis.

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“…This large 21-MDa nuclear ribonucleoprotein complex (24) has been proposed to constitute the machine where RNA splicing occurs in living cells. In addition to its splicing activity (25), the supraspliceosome harbors other pre-mRNA processing components including the editing enzymes ADAR1 and ADAR2 and the A-to-I editing activity associated with them (26,27). We therefore asked whether the hUpf and the ADAR proteins, which are involved in apparently distinct RNA processing functions, interact within the supraspliceosome.…”

mentioning

confidence: 99%

The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus

Agranat

Raitskin

Sperling

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Posttranscriptional regulation is an important step in the regulation of gene expression. In this article, we show an unexpected connection between two proteins that participate in different processes of posttranscriptional regulation that ensures the production of functional mRNA molecules. Specifically, we show that the A-to-I RNA editing protein adenosine deaminase that acts on RNA 1 (ADAR1) and the human Upf1 (hUpf1) protein involved in RNA surveillance are found associated within nuclear RNA-splicing complexes. A potential functional role for this association was revealed by RNAi-mediated down-regulation of ADAR1, which was accompanied by up-regulation of a number of genes previously shown to undergo A-to-I editing in Alu repeats and to be downregulated by hUpf1. This study suggests a regulatory pathway by a combination of ADAR1 A-to-I editing enzyme and RNA degradation presumably with the aid of hUpf1.RNAi ͉ supraspliceosomes ͉ posttranscriptional regulation ͉ nuclear complexes ͉ cross-linking R NA editing catalyzed by the adenosine deaminase that acts on RNA (ADAR) family of proteins involves the conversion of adenosines to inosines (A to I) and is one of the pre-mRNA processing activities. Of the three identified human ADAR proteins, ADAR1 and ADAR2 are expressed ubiquitously and have different isoforms resulting from alternative splicing, whereas ADAR3 is expressed at low levels only in the brain (reviewed in refs. 1 and 2). ADAR1 exists in two major forms expressed from two distinct promoters. The IFN-induced longer one is present both in the nucleus and cytoplasm, whereas the constitutively expressed shorter one is present in the nucleus (3, 4).ADARs act on double-stranded RNA and deaminate adenosines at specific sites. Because inosines are generally basepaired to cytidines, specific A-to-I editing can change the coding potential within an ORF, or change splice sites and other control elements (1, 2). A functional significance of the specific editing by ADARs is exemplified by the dramatic decrease of Ca 2ϩ permeability of the AMPA channel by editing of the Q/R site of GluR-B subunit (5). Significant changes in the G protein coupling efficiency of 5-HT 2C R have also been reported (6, 7). However, in many other substrates, A-to-I editing was found clustered in noncoding regions mainly in Alu repetitive elements (8-11), as expected from the identification of a large number of inosines in mRNA molecules (12). The functional significance of the latter editing is not yet fully understood. Some of the editing in noncoding regions was suggested as part of a protection mechanism of mRNA molecules against RNAi-like degradation (13). ADARs were also shown to bind siRNA and were thus proposed to protect mRNA molecules from RNAi-like degradation (14). However, double-stranded RNA molecules with repeating U-I base pairs undergo degradation mediated by Tudor, one of the RNA-induced silencing complex (RISC) components (15). Pan-editing by the IFN-induced ADAR1 was proposed as part of the antiviral protection mechan...

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RNA editing activity is associated with splicing factors in lnRNP particles: The nuclear pre-mRNA processing machinery

Cited by 83 publications

References 42 publications

Widespread RNA Editing of Embedded Alu Elements in the Human Transcriptome

Widespread RNA Editing of Embedded Alu Elements in the Human Transcriptome

Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene

The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus

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