共查询到20条相似文献,搜索用时 46 毫秒
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ADAR enzymes, adenosine deaminases that act on RNA, form a family of RNA editing enzymes that convert adenosine to inosine within RNA that is completely or largely double-stranded. Site-selective A→I editing has been detected at specific sites within a few structured pre-mRNAs of metazoans. We have analyzed the editing selectivity of ADAR enzymes and have chosen to study the naturally edited R/G site in the pre-mRNA of the glutamate receptor subunit B (GluR-B). A comparison of editing by ADAR1 and ADAR2 revealed differences in the specificity of editing. Our results show that ADAR2 selectively edits the R/G site, while ADAR1 edits more promiscuously at several other adenosines in the double-stranded stem. To further understand the mechanism of selective ADAR2 editing we have investigated the importance of internal loops in the RNA substrate. We have found that the immediate structure surrounding the editing site is important. A purine opposite to the editing site has a negative effect on both selectivity and efficiency of editing. More distant internal loops in the substrate were found to have minor effects on site selectivity, while efficiency of editing was found to be influenced. Finally, changes in the RNA structure that affected editing did not alter the binding abilities of ADAR2. Overall these findings suggest that binding and catalysis are independent events. 相似文献
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(1) Pre-mRNA editing of serotonin 2C (5-HT2C) and glutamate (Glu) receptors (R) influences higher brain functions and pathological states such as epilepsy, amyotrophic
lateral sclerosis, and depression. Adenosine deaminases acting on RNA (ADAR1–3) convert adenosine to inosine on synthetic
RNAs, analogous to 5-HT2cR and GluR. The order of editing as well as mechanisms controlling editing in native neurons is unknown. (2) With single-cell
RT-PCR we investigated the co-expression of ADAR genes with GluR and 5-HT2CR and determined the editing status at known sites in the hypothalamic tuberomamillary nucleus, a major center for wakefulness
and arousal. (3) The most frequently expressed enzymes were ADAR1, followed by ADAR2. The Q/R site of GluR2 was always fully
edited. Editing at the R/G site in the GluR2 (but not GluR4) subunit was co-ordinated with ADAR expression: maximal editing
was found in neurons expressing both ADAR2 splice variants of the deaminase domain and lacking ADAR3. (4) Editing of the 5-HT2CR did not correlate with ADAR expression. The 5-HT2CR mRNA was always edited at A, in the majority of cells at B sites and variably edited at E, C and D sites. A negative correlation
was found between editing of C and D sites. The GluR4 R/G site editing was homogeneous within individuals: it was fully edited
in all neurons obtained from 12 rats and under-edited in six neurons obtained from three rats. (5) We conclude that GluR2
R/G editing is controlled at the level of ADAR2 and therefore this enzyme may be a target for pharmacotherapy. On the other
hand, further factors/enzymes besides ADAR must control or influence 5-HT2CR and GluR pre-mRNA editing in native neurons; our data indicate that these factors vary between individuals and could be
predictors of psychiatric disease. 相似文献
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Peng PL Zhong X Tu W Soundarapandian MM Molner P Zhu D Lau L Liu S Liu F Lu Y 《Neuron》2006,49(5):719-733
ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca2+ entry through AMPA receptor channels. Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons. Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult. Generation of a stable ADAR2 gene silencing by delivering small interfering RNA (siRNA) inhibits GluR2 Q/R site editing, leading to degeneration of ischemia-insensitive neurons. Direct introduction of the Q/R site edited GluR2 gene, GluR2(R607), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia. 相似文献
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Marcucci R Brindle J Paro S Casadio A Hempel S Morrice N Bisso A Keegan LP Del Sal G O'Connell MA 《The EMBO journal》2011,30(20):4211-4222
ADAR2 catalyses the deamination of adenosine to inosine at the GluR2 Q/R site in the pre-mRNA encoding the critical subunit of AMPA receptors. Among ADAR2 substrates this is the vital one as editing at this position is indispensable for normal brain function. However, the regulation of ADAR2 post-translationally remains to be elucidated. We demonstrate that the phosphorylation-dependent prolyl-isomerase Pin1 interacts with ADAR2 and is a positive regulator required for the nuclear localization and stability of ADAR2. Pin1(-/-) mouse embryonic fibroblasts show mislocalization of ADAR2 in the cytoplasm and reduced editing at the GluR2 Q/R and R/G sites. The E3 ubiquitin ligase WWP2 plays a negative role by binding to ADAR2 and catalysing its ubiquitination and subsequent degradation. Therefore, ADAR2 protein levels and catalytic activity are coordinately regulated in a positive manner by Pin1 and negatively by WWP2 and this may have downstream effects on the function of GluR2. Pin1 and WWP2 also regulate the large subunit of RNA Pol II, so these proteins may also coordinately regulate other key cellular proteins. 相似文献
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Mats Ensterö Örjan Åkerborg Daniel Lundin Bei Wang Terrence S Furey Marie Öhman Jens Lagergren 《BMC bioinformatics》2010,11(1):6