Eukaryotes possess a vast array of RNA-binding proteins (RBPs) that affect mRNAs in diverse ways to control protein expression. Combinatorial regulation of mRNAs by RBPs is emerging as the rule. No example illustrates this as vividly as the partnership of 3 Drosophila RBPs, Pumilio, Nanos and Brain Tumor, which have overlapping functions in development, stem cell maintenance and differentiation, fertility and neurologic processes. Here we synthesize 30 y of research with new insights into their molecular functions and mechanisms of action. First, we provide an overview of the key properties of each RBP. Next, we present a detailed analysis of their collaborative regulatory mechanism using a classic example of the developmental morphogen, hunchback, which is spatially and temporally regulated by the trio during embryogenesis. New biochemical, structural and functional analyses provide insights into RNA recognition, cooperativity, and regulatory mechanisms. We integrate these data into a model of combinatorial RNA binding and regulation of translation and mRNA decay. We then use this information, transcriptome wide analyses and bioinformatics predictions to assess the global impact of Pumilio, Nanos and Brain Tumor on gene regulation. Together, the results support pervasive, dynamic post-transcriptional control.
Bibliographical noteFunding Information:
This research was supported by grant R01GM105707 from the National Institute of General Medical Sciences, National Institutes of Health (ACG), Research Scholar Grant from RSG-13–080–01-RMC from the American Cancer Society (ACG), and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (TMTH). RenéM. Arvola is supported by graduate research fellowship DGE 1256260 from the National Science Foundation. We sincerely apologize to colleagues whose work we were unable to include due to space limitations.
- Brain Tumor (or Brat)
- combinatorial mRNA regulation
- cooperative RNA binding