ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs

Vitali, Patrice; Basyuk, Eugénia; Meur, Elodie Le; Bertrand, Édouard; Muscatelli, Françoise; Cavaillé, Jérôme; Hüttenhofer, Alexander

doi:10.1083/jcb.200411129

Cited by 209 publications

(216 citation statements)

References 62 publications

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“…On the basis of our observations that ADAR1 colocalizes with SUMO-1 in the nucleolus and that sumoylation of ADAR1 reduces editing activity, we propose that the nucleolus represents a "sink" for inactive ADAR1 in the cell. In agreement with this view, it has been recently reported that ADAR2-but not ADAR1-mediated RNA editing occurs in the nucleolus (Vitali et al, 2005). Considering that both ADAR1 and ADAR2 colocalize in the nucleolus, it was unexpected to find that ADAR1 does not perform nucleolar RNA editing.…”

Section: Discussionmentioning

confidence: 52%

SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

103

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We identify ADAR1, an RNA-editing enzyme with transient nucleolar localization, as a novel substrate for sumoylation. We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component. Our results further show that human ADAR1 is modified by SUMO-1 on lysine residue 418. An arginine substitution of K418 abolishes SUMO-1 conjugation and although it does not interfere with ADAR1 proper localization, it stimulates the ability of the enzyme to edit RNA both in vivo and in vitro. Moreover, modification of wild-type recombinant ADAR1 by SUMO-1 reduces the editing activity of the enzyme in vitro. Taken together these data suggest a novel role for sumoylation in regulating RNA-editing activity. INTRODUCTIONA defining feature of eukaryotic cells is the generation of protein diversity either posttranscriptionally by alternative splicing and RNA editing or posttranslationally by modification of amino acids in proteins. One of the most recently discovered posttranslational modification mechanism in eukaryotes involves the covalent attachment of the small ubiquitinlike modifier, SUMO, to target proteins. Modification of proteins by SUMO, or sumoylation, plays crucial regulatory roles in eukaryotes. Proteins known to be modified by SUMO include, among others, RanGAP1, PCNA, I B␣, p53, c-jun, topoisomerases, promyelocytic leukemia protein (PML), Sp100, and the mitogen-activated protein kinase kinase 1 (MEKK1). Many SUMO substrates are transcription factors and cofactors, or proteins implicated in DNA repair and replication (reviewed by Hay, 2001;Melchior et al., 2003;Seeler and Dejean, 2003;Hay, 2005). Although it is well established that SUMO can affect target protein function by altering its subcellular localization, activity, or stability, for many substrates the biological functions of sumoylation remain unknown.Sumoylation is a reversible and highly dynamic process that involves formation of an isopeptide bond between the C-terminus of SUMO and the ⑀-amino group of a lysine residue of the target protein. The most intensely studied human form of SUMO is the SUMO-1 protein, which is 48% identical to yeast Smt3 (Bayer et al., 1998;Mossessova and Lima, 2000). In vertebrates there are at least three additional proteins. SUMO-2 and SUMO-3 are ϳ45% identical to SUMO-1 (Saitoh and Hinchey, 2000), and SUMO-4 shows an 86% amino acid homology to SUMO-2 (Bohren et al., 2004). SUMO is conjugated to protein substrates via an ATP-dependent enzymatic pathway that is mechanistically similar to ubiquitination. The reaction requires a SUMO protease that removes four amino acids from the C-terminus of the 101-amino acid SUMO-1 precursor to generate the mature form; an heterodimeric SUMO-activating enzyme, SAE1/2; Ubc9, a SUMO-conjugating enzyme that ligates directly to its protein target; and an E3-like SUMO ligase (reviewed Melchior et al., 2003). Three SUMO E3s have been identified so far: the mammalian protein inhibitors of activated S...

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Section: Discussionmentioning

confidence: 52%

SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

103

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“…Differences may arise, however, from changes in the levels of ADAR proteins and/or their enzymatic activities, or from other factors that have been shown to be involved in regulating the editing process (for example, small nucleolus RNA HBII-52, RNA helicase A). 17,41 Thus, a number of candidate targets can be identified for future investigation.…”

Section: Discussionmentioning

confidence: 99%

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

et al. 2007

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Suicide is a major public health problem with B1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2C R mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.

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“…All eukaryotes contain orphan snoRNAs, which do not have complementarity to rRNAs or snRNAs. In animals, such snoRNAs have been found to be involved in RNA editing, alternative splicing, and regulation of gene expression (Vitali et al, 2005;Kishore and Stamm, 2006;Ender et al, 2008;Saraiya and Wang, 2008;Ono et al, 2010). Recently, three mammalian snoRNAs (all encoded in the introns of a ribosomal protein gene) were shown to be involved in regulation of metabolic stress response (Michel et al, 2011).…”

Section: Rna Complexity In the Nucleolusmentioning

confidence: 99%