High-throughput siRNA screening reveals functional interactions and redundancies of human processive exoribonucleases

Processive exoribonucleases, the executors of RNA decay, participate in multiple physical and functional interactions. Unlike physical ones, functional relationships have not been investigated in human cells. Here we have screened cells deficient in DIS3, XRN2, EXOSC10, DIS3L, and DIS3L2 with a custom siRNA library and determined their functional interactions with diverse pathways of RNA metabolism. We uncover a complex network of positive interactions that buffer alterations in RNA degradation. We reveal important reciprocal actions between RNA decay and transcription and explore alleviating interactions between RNA splicing and DIS3 mediated degradation. We also use a large scale library of genes associated with RNA metabolism to determine genetic interactions of nuclear DIS3 and cytoplasmic DIS3L, revealing their unique functions in RNA degradation and uncovering cooperation between the cytoplasmic degradation and nuclear processing of RNA. Finally, genome-wide siRNA screening of DIS3 reveals processes such as microtubule organization and regulation of telomerase activity that are also functionally associated with nuclear exosome-mediated RNA degradation.