Landscape of functional interactions of human processive ribonucleases revealed by high-throughput siRNA screenings

Processive exoribonucleases are executors of RNA decay. In humans, their physical but not functional interactions were thoughtfully investigated. Here we have screened cells deficient in DIS3, XRN2, EXOSC10, DIS3L, and DIS3L2 with a custom siRNA library and determined their genetic interactions (GIs) with diverse pathways of RNA metabolism. We uncovered a complex network of positive interactions that buffer alterations in RNA degradation and reveal reciprocal cooperation with genes involved in transcription, RNA export, and splicing. Further, we evaluated the functional distinctness of nuclear DIS3 and cytoplasmic DIS3L using a library of all known genes associated with RNA metabolism. Our analysis revealed that DIS3 mutation suppresses RNA splicing deficiency, while DIS3L GIs disclose the interplay of cytoplasmic RNA degradation with nuclear RNA processing. Finally, genome-wide DIS3 GI map uncovered relations with genes not directly involved in RNA metabolism, like microtubule organization or regulation of telomerase activity.