“The piRNA Pathway: a Small RNA-Based Innate Immune System”. Greg Hannon. HHMI, Cold Spring Harbor Lab, One Bungtown Road, Cold Spring Harbor, NY.

   PIWI-family proteins and their associated small RNAs (piRNAs) act in an evolutionarily conserved innate immune mechanism that provides an essential protection for germ cell genomes against the activity of mobile genetic elements. piRNA populations comprise a molecular definition of transposons that permits them to be distinguished from host genes and selectively silenced. piRNAs can be generated in two distinct ways. Primary piRNAs emanate from discrete genomic loci, termed piRNA clusters, and appear to be derived from long, single-stranded precursors. The biogenesis of primary piRNAs involves at least two nucleolytic steps. An unknown enzyme cleaves piRNA cluster transcripts to generate monophosphorylated piRNA 5 ends. piRNA 3 ends are likely formed by exonucleolytic trimming, after a piRNA precursor is loaded into its PIWI partner. Secondary piRNAs arise during the adaptive ping-pong cycle, with their 5 termini being formed by the activity of PIWIs themselves. At least in Drosophila, piRNAs are maternally deposited and transmit an epigenetic signal essential for the effective control of at least some transposable elements. I will describe our recent efforts, which bring to bear biochemical, structural, and genetic strategies in an effort to understand how piRNAs are formed and the mechanisms by which they recognize and silence their targets.