“the 'Hannon trilogy' — ...all you need to know to understand how dsRNA directs the sequence-specific inhibition of gene expression”

When facing the challenge of introducing the basics of RNA silencing to a new student, I often resort to what I call the 'Hannon trilogy' — a set of 3 papers, among my all-time favourites, which contain essentially all you need to know to understand how double-stranded (ds) RNA directs the sequence-specific inhibition of gene expression in most eukaryotic cells. The first paper, by Bernstein et al., establishes that dsRNA is processed into small ( 20 nucleotide) RNAs by an RNase III enzyme called Dicer. The second two papers, both by Hammond et al., show that the small RNAs, following their incorporation into the Argonaute (AGO) nuclease, then guide an RNA-induced silencing complex (RISC) to destroy the complementary mRNA. I sometimes re-read these articles with nostalgia, as the formidable mechanistic insight they provided at the time signalled the twilight of the 'romantic phase' of RNA silencing — the not-so-distant time of my Ph.D. studies, when the many manifestations of RNA silencing that had just been described in various organisms were still mechanistically mysterious, and not necessarily appreciated as being related.

In fact, the transition to the 'modern phase' of RNA silencing started with the discovery in plants, by Hamilton and Baulcombe, of what would later be renamed small interfering RNAs (siRNAs). The development of powerful in vitro assays and access to genomic information in model organisms, notably in flies, then expedited the identification of the molecular machines that generate siRNAs and execute their functions, an endeavour to which the Hannon group contributed substantially. This, ultimately, greatly facilitated the identification of endogenous siRNA-like molecules known as microRNAs, which regulate many key aspects of eukaryotic biology.

So, when my students come back to me with sparkling eyes and all sorts of questions, I know that, yet again, the Hannon trilogy has done a great job.