The signature of gene misregulation in rde-4 mutant L1-L2 larvae significantly overlaps with that of zfp-1 loss-of-function mutants ( Grishok et al., 2008). Consistently, rde-4 mutants have a decreased life span ( Mansisidor et al., 2011 Welker et al., 2007) and an increased sensitivity to oxidative stress, pathogens ( Mansisidor et al., 2011), and elevated temperatures ( Blanchard et al., 2011). Microarray studies performed on rde-4-null worms identified a connection to regulation of stress response ( Grishok et al., 2008 Mansisidor et al., 2011 Welker et al., 2007). Moreover, rde-4 is required for the maximum accumulation of 22G-RNAs produced by the germline RdRP EGO-1 ( Maniar & Fire, 2011). RDE-4 functions with RDE-1 in the rare cases when this Argonaute is involved in gene regulation ( Correa et al., 2010 Gu et al., 2009), and it also coimmunoprecipitates with ERI-1 and ERI-5 ( Thivierge et al., 2012) and is required for 26G production ( Vasale et al., 2010). Their expression may vary at different development stages or in different tissues, suggesting that the roles of Argonaute proteins are diversified in RNA silencing ( Lee et al., 2003 Sasaki et al., 2003 Williams and Rubin, 2002).Īlla Grishok, in Advances in Genetics, 2013 3.3.4 Endogenous RNAi and adaptation to environmentĪlthough the role of RDE-4 in exo-RNAi is understood relatively well (see Section 3.1.1 ), its contribution to endogenous RNAi pathways is defined less clearly. elegans has five ( Williams and Rubin, 2002), human has eight ( Sasaki et al., 2003), and Drosophila has 23 ( Williams and Rubin, 2002) members of Argonaute proteins, respectively. Multiple Argounaute-like proteins are commonly found in the genomes from organisms with an RNA silencing pathway. Moreover, the mutation of Ago1 reduced the ability of Drosophila embryo cells in degrading mRNA molecules but not in producing siRNAs ( Williams and Rubin, 2002). In addition, QDE-2 could be copurified with siRNAs ( Catalanotto et al., 2002). Evidences supporting such a mechanism include that QDE-1 and QDE-3, but not QDE-2, are responsible for accumulation of the essential siRNAs in N. Indeed, the Argonaute proteins are involved in the downstream mRNA degradation, but not the generation of siRNAs, in the RNAi pathway. This is suggestive of a direct role of the Argonaute proteins in RNAi-mediated gene silencing. The Argonaute proteins reside in the RNA-induced silencing complex (RISC), as have been shown for the Drosophila Ago2 ( Hammond et al., 2001). The carboxy-terminus region of QDE-2 shares 38% similarity with an E-value of 10 −23 to that of RDE-1 ( Catalanotto et al., 2000), which is essential for RNAi in C. Argonaute proteins are typically composed of four domains: an N-terminal domain, a PAZ (PIWI/Argonaute/Zwille, where PIWI stands for “P-element-induced wimpy testis”) domain binding to the 3′-end of guide RNAs, an MID (middle) domain forming a pocket for the 5′-phosphate of guide RNAs, and the PIWI domain with endonucleolytic activity ( Boland et al., 2010). elegans, Ago1 from Arabidopsis, and Ago2 from Drosophila, belongs to the Argonaute protein family ( Carmell et al., 2002). crassa QDE-2, in addition to its homologs RDE-1 from C. Zhiyang Dong, in Biotechnology and Biology of Trichoderma, 2014 Quelling Defective-2 (QDE-2) Developmental functions have not been reported thus far. elegans ( Ashe et al., 2013 Sarkies, Ashe, Le Pen, McKie, & Miska, 2013). Finally, we note that this pathway is an important weapon against exogenous pathogens, as it is required for virus control in C. Why target cleavage is handed over to another protein while RDE-1 itself could also cleave is unclear, but could be related to the fact that the targeted RNA needs to be marked as a template for an RdRP to generate the secondary 22G-RNAs, that are loaded into different WAGO proteins. How then does RDE-1 silence its targets? The NYN-domain nucleases, such as RDE-8, NYN-1 and NYN-2, are required for this ( Tsai et al., 2015). Rather, its enzymatic activity is needed to remove one of the two siRNA strands following loading of an siRNA duplex ( Steiner, Okihara, Hoogstrate, Sijen, & Ketting, 2009). RDE-1 is a cleavage competent Argonaute protein, but this activity is dispensable for target silencing. RDE-1 is loaded with short interfering RNAs (siRNAs) directly produced from the administered dsRNA, through the action of Dicer ( Grishok et al., 2001 Ketting et al., 2001 Knight & Bass, 2001 Tabara, Yigit, Siomi, & Mello, 2002 Yigit et al., 2006). Ketting, Luisa Cochella, in Current Topics in Developmental Biology, 2021 3.2 The exo-RNAi pathway (or the RDE-1 pathway)Įxo-RNAi requires the primary Argonaute RDE-1 ( Tabara et al., 1999).
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