Abstract
When a field shares the consensus that a particular phenomenon does NOT occur, this may reflect extensive experimental investigations with negative outcomes, or may represent the “common sense” position based on current knowledge and established ways of thinking. The current consensus of the RNA field is that eukaryotic Argonaute (Ago) proteins employ RNA guides and target other RNAs. The alternative -- that eukaryotic Ago has biologically important interactions with DNA in vivo – has not been seriously considered, in part because the only role contemplated for DNA was as a guide strand, and in part because it did not seem plausible that any natural source of suitable DNAs exists in eukaryotic cells. However, eukaryotic Argonaute domains bind DNA in the test tube, and several articles report that small inhibitory double-stranded DNAs do have the ability to silence target RNAs in a sequence-dependent (though poorly characterized) manner. A search of the literature identified potential DNA binding partners for Ago, including (among others) single-stranded DNAs residing in extracellular vesicles, and cytoplasmic satellite-repeat DNA fragments that are associated with the plasma membrane and transcribed by Pol II. It is interesting to note that both cytoplasmic and extracellular vesicle DNA are expressed at greatly elevated levels in cancer cells relative to normal cells. In such a pathological scenario, if not under normal conditions, there may be appreciable binding of Ago to DNA despite its lower affinity compared to RNA. If so, DNA might displace Ago from binding to its normal partners (miRNAs, siRNAs and other short ncRNAs), disrupting tightly controlled post-transcriptional gene silencing processes that are vital to correct functioning of a normal cell. The possible contribution to cancer pathogenesis is a strong motivator for further investigation of Ago-DNA binding. More generally, this case underscores the need for better informatics tools to allow investigators to analyze the state of a given scientific question at a high-level and to identify possible new research directions.Reviewers: This article was reviewed by Eugene Koonin, Kira S. Makarova, Alexander Maxwell Burroughs (nominated by L Aravind), and Isidore Rigoutsos.Open peer review: Reviewed by Eugene Koonin, Kira S. Makarova, Alexander Maxwell Burroughs (nominated by L Aravind), and Isidore Rigoutsos. For the full reviews, please go to the Reviewers’ comments section.
Highlights
Analyses of new emerging scientific research trends are almost always done retrospectively, rather than prospectively
When we took a peek into the literature in search of potential DNA binding partners for Ago, we found an assortment of odd characters worthy of the Exploding Plastic Inevitable, whose very existence are poorly characterized and hard to fit within existing scientific frameworks: small inhibitory DNA (siDNA); single-stranded DNAs residing in extracellular vesicles; and satellite-repeat DNA fragments that are associated with the plasma membrane and transcribed by Pol II, to name three
Implications for the informatics of scientific discovery A second underlying purpose in writing the present article is to evaluate the literature surrounding a specific situation in biology, with an eye towards understanding the needs and requirements for developing new informatics tools that can assist investigators in scientific discovery [58,59,60,61]
Summary
Analyses of new emerging scientific research trends are almost always done retrospectively, rather than prospectively. The starting point for our analysis is the publication of two breakthrough papers (Olovnikov et al [1]; Swarts et al [2]), which provided experimental validation of predictions made previously by Makarova et al [3], namely, that prokaryotic Argonaute proteins are able to bind DNA and to carry out DNA-guided as well as RNAguided mediated cleavage of DNA molecules (“DNA interference”) [1,2,3] This appears to provide a form of protection of a bacterial cell against foreign invading plasmids and possibly other sources of foreign DNA. It is interesting to note that both cytoplasmic DNA and extracellular vesicle DNA are expressed at greatly elevated levels in cancer cells relative to normal cells In such a pathological scenario, if not under normal conditions, there may be appreciable binding of Ago to DNA despite its lower affinity compared to RNA. The possible contribution to cancer pathogenesis is a strong motivator for further investigation of Ago-DNA binding
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