The biological significance of repetitive RNA editing is largely unknown, but examples have shown involvement in RNA induced gene silencing (RNAi) and microRNA (miRNA) modulation, stabilization of mRNA and nuclear retention (Figure 4) [38]. Viral RNA is also often deaminated by host ADARs which has pro- or antiviral effects depending on the specific type of virus (Figure 4) [39]. Since the identification of ADAR and ADAT enzymes in the early

90s, the presence and importance of inosine in RNA have been well recognised [31]. A-to-I editing of RNA substrates are rarely complete and it appears that ADAR activity is dynamically regulated through yet poorly U0126 understood mechanisms [34]. In addition to tight regulation of ADAR activity, specific destruction of A-to-I edited transcripts could be a way to control the level of editing. Anti-diabetic Compound Library nmr Until very recently, no such activity was proven. Last year, Morita et al. [ 40••] and Vik et al. [ 41••] both demonstrated efficient cleavage of inosine-containing RNA by human EndoV suggesting that EndoV could fulfill such a role ( Figure 2b). The cytosolic localization of hEndoV supports this notion [ 42]. Another protein, the Tudor staphylococcal nuclease 1 (Tudor-SN) has also been linked to processing of inosine-containing RNA [ 43 and 44] ( Figure 2b). Tudor-SN was initially identified in extracts from Xenopus laevis by its ability to bind inosine-containing RNA [ 43]. Tudor-SN has five staphylococcal

nuclease-like domains (SN1–5) in addition to one tudor domain and is a multifunctional protein participating in diverse processes including RNAi, transcriptional coactivation and mRNA splicing [ 45]. The specific activity for Tudor-SN for inosine-containing RNA has not been

thoroughly addressed and the individual contribution of EndoV and Tudor-SN remains to be elucidated. The concentrations of cellular nucleotides are highly controlled [46 and 47]. Defects in genes involved in the nucleotide metabolism and imbalance in the nucleotide pools are found in several human diseases such as immunodeficiency, hyperuricemia with neurological DOK2 symptoms (Lech-Nyman syndrome) and several types of cancer [48 and 49]. One possible mechanism underlying these pathologies involves the formation of non-canonical NTPs with subsequent incorporation into DNA and RNA contributing to mutagenesis and carcinogenesis. Cells express enzymes counteracting such threats, for example inosine triphosphate pyrophosphatase (ITPA in mammalian cells, RdgB in E. coli) that hydrolyses dITP to its monophosphate form. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental abnormalities [ 50]. It has been shown that Itpa−/− mice accumulates inosine in DNA and RNA [ 51• and 52]. In contrast, ITPA deficiency in human is seemingly innocuous, but has been linked to psychological disorders [ 53] and overexpression of ITPA is seen in several cancers [ 54].