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Archived Comments for: The dose can make the poison: lessons learned from adverse in vivotoxicities caused by RNAi overexpression

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  1. Small RNAs-cell physiology, a dual analog of dose-response kinetics.

    Christos Kotakis, University of Crete

    30 November 2011

    Currently, I read the interesting minireview by Grimm in Silence journal (doi:10.1186/1758-907X-2-8), concerning siRNAs¿ toxic effects in cell vitality as it was probed in vivo. According to this paper, it has been collectively reported in different works that the desirable effect of RNAi bioassays is dependent on the small RNAs¿ dosage. In other words, there are some limitations in the efficiency of small RNAs¿ action per se, due to a `saturating¿ plateau referring, not only to the RNA silencing mechanism sensitivity but also in the consequences of those universal `entities¿ on cellular homeostasis.
    Far away from transgenic constructions, let¿s give a glance at the role of endogenous non-coding RNAs in a wild-type cell; it ranges from the `buffering¿ the genome integrity (Ha et al., 2009) to the synergistic interaction between nucleus and subcellular organelles (e.g. mitochondrion), (Rackham et al., 2011). The diversity of those biological circumstances imposes the need for other also aspects of this `RNA component¿ to be integrated, besides the mechanistic principles of RNA silencing itself.
    In parallel with the contribution of Grimm and being inspired by various examples of ecological extremity in time and space that sequentially affects small RNAs¿ performance; I would like to pose a hypothesis, as you can follow:
    The dynamic micro-environmental conditions inside the intra-/inter-cellular space make likely the RNA silencing machinery to behave as a dynamic `rheostat¿ resulting on oscillative small RNAs¿ populations. Taking into account that the biophysical and the structural features of bona fide siRNAs are evolutionary conserved among different eukaryotes (Tang and Zamore, 2004), the small RNA pool maybe has to be considered as a biochemical `ontogeny¿, in a quantitative view. Such approaches could be followed, independently of the (model) organism and the physiological condition studied. For instance, the involvement of magnesium ions in RISC activity (reviewed by Kawamata and Tomari, 2010) as well as the Michaelis-Menten turnover properties of the last (Haley and Zamore, 2004; Brown et al., 2005) could be combined by a such logic.
    Towards this aim, I am wondering if a functional correlation can be supported between non-coding RNAs and the evolutionary formation of mRNP granules (P-bodies and stress granules), (reviewed by Erickson and Lykke-Andersen, 2011) due to such phenomena mentioned above.

    Competing interests

    None declared