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

Abstract

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.

Editor meets silencer: crosstalk between RNA editing and RNA interference

“…Following their incorporation into RISC, miRNAs block the translation of partially complementary targets that are located in the 3′ UTR of specific mRNAs or they guide the degradation of target mRNAs, as do siRNAs [12][13][14][15][16] . Any dsRNAs that are recognized by the RNAi mechanism are also potential targets for A→I RNA editing, and the possibility that pri-miRNAs might be edited by ADAR has been pointed out previously 61 .…”

“…The inactivation of Adar1 leads to an embryonic lethal phenotype, which is caused by widespread apoptosis [60][61][62] . It seems that the editing of currently unknown target dsRNA(s) protects developing embryos from massive apoptosis.…”

“…3a). Last, the inactivation of ADAR1 leads to an embryonic lethal phenotype that is caused by defective erythropoiesis and widespread apoptosis [60][61][62] .…”

“…3a). Last, the inactivation of ADAR1 leads to an embryonic lethal phenotype that is caused by defective erythropoiesis and widespread apoptosis [60][61][62] .Human diseases or pathophysiologies can also be caused by dysfunction of the A→I RNA editing mechanism 63,64 . Heterozygosity for the ADAR1-gene functional-null mutation results in dyschromatosis symmetrica hereditaria, a human pigmentary genodermatosis of autosomaldominant inheritance 65 .…”

“…A large new class of small RNAs (∼26-30 nucleotides) in complex with PIWI-family proteins (piRNAs, PIWI-interacting RNAs) has been reported in mammalian testes 92,[101][102][103] . It would be interesting to determine whether A→I RNA editing is at all involved in the suppression of piRNA biogenesis.The inactivation of Adar1 leads to an embryonic lethal phenotype, which is caused by widespread apoptosis [60][61][62] . It seems that the editing of currently unknown target dsRNA(s) protects developing embryos from massive apoptosis.…”