Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems

Abstract

Recent evidence supports that prokaryotes exhibit adaptive immunity in the form of CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats) and Cas (CRISPR associated proteins). The CRISPR-Cas system confers resistance to exogenous genetic elements such as phages and plasmids by allowing for the recognition and silencing of these genetic elements. Moreover, CRISPR-Cas serves as a memory of past exposures. This suggests that the evolution of the immune system has counterparts among the prokaryotes, not exclusively among eukaryotes. Mathematical models have been proposed which simulate the evolutionary patterns of CRISPR, however large gaps in our understanding of CRISPR-Cas function and evolution still exist. The CRISPR-Cas system is analogous to small RNAs involved in resistance mechanisms throughout the tree of life, and a deeper understanding of the evolution of small RNA pathways is necessary before the relationship between these convergent systems is to be determined. Presented in this review are novel RNAi therapies based on CRISPR-Cas analogs and the potential for future therapies based on CRISPR-Cas system components.

When Competing Viruses Unify: Evolution, Conservation, and Plasticity of Genetic Identities

“…And this world must also have created DNA. Several investigators have noted the striking strategic similarities between the RNA-based defense systems of prokaryotes and eukaryotes (Karginov and Hannon 2010;Cooper and Overstreet 2014;Koonin and Krupovic 2014). Yet these systems share no homology with each other and must have derived from distinct ancestors.…”

Knowledge-based discovery for designing CRISPR-CAS systems against invading mobilomes in thermophiles

“…Archaeal specific genes (csa1-csa5) reported to show a degree of specificity across archaeal or bacterial phyla (Bolotin et al 2005;Haft et al 2005;Cooper and Overstreet 2014). Therefore, the cas genes of most thermophilic genomes have appeared in the order of cas5-cas3-cas1-cas2.…”

“…The common structural characteristics of CRISPR loci are: (1) multiple short direct repeats (2) non-repetitive spacer sequences between the repeats of similar size (3) a common leader sequence of a few hundred base pairs harboring multiple CRISPR loci and (4) accompanied by cas gene families. The principal products of the CRISPR loci are comprised primarily of invader-targeting sequences that are likely the guides for effector complexes of pRNAi system (Hale et al 2008;Quax et al 2013;Cooper and Overstreet 2014). CRISPR-CAS systems confer viral resistance in these genomes remain hypothetical and undefined.…”

“…Clustered regularly interspaced short palindromic repeats (CRISPRs) have played an important role in the chromosomal rearrangement, DNA mobilization, repair and regulation and also replicon partitioning (Haft et al 2005;DeBoy et al 2006;Makarova et al 2006;Cooper and Overstreet 2014). Among 25 gene families in the CAS system, eight gene families (cas1, cas2, cas4, cas6, cas7) have reported for the nuclease activity, nine families (cas5) for Repeat-Associated Mysterious Proteins (RAMP) and two families (cas3) for DNA/RNA polymerase/helicase activity (Makarova et al 2006;Quax et al 2013;Vestergaard et al 2014).…”

The double-edged sword of Lamarck

“…As it so often happens in the history of science, it all changed abruptly in 2006–2007, not through focused efforts to demonstrate the reality of Lamarckian evolution, but as a result of the unexpected discovery of adaptive immunity in bacteria and archaea. This form of immunity in prokaryotes is mediated by the CRISPR–Cas ( c lustered r egularly i nterspaced s hort p alindromic r epeats and C RISPR- as sociated genes) system [2–4] that is discussed in detail and compared to other immunity systems in the timely review article by Cooper and Overstreet [5]. …”