DND1–NANOS3 shapes the PGC transcriptome via a heptanucleotide sequence in mRNA 3′-UTRs

Abstract

Summary: Primordial germ cell survival requires joint function of the RNA-binding proteins DND1 and NANOS3; yet, how they collaborate was not established. Here, we discover a paradigm of “two-factor authorization”, where RNA-binding proteins with low (DND1) or no (NANOS3) sequence-specificity jointly repress RNAs via a unique high-information-content motif. Tandem PAR-CLIP showed that a DND1–NANOS3 complex represses mRNAs of dozens of key epigenome and cell-cycle regulators, recognizing a heptamer (AUGAAUU) in their 3′-UTRs. Genome editing of this element relieved DND1–NANOS3-mediated repression of CDK1 in vivo. A high-resolution structure revealed a continuous RNA-binding surface formed by DND1 and NANOS3, and biochemical analysis indicated that a NANOS3 intrinsically-disordered region contributes to high-affinity and sequence-specificity of the complex. RNA-binding proteins are typically studied individually, thus missing new specificities imparted by ribonucleoprotein complex formation. Our study hints that two-factor authorization is an underappreciated regulatory mechanism for safeguarding against aberrant expression of post-transcriptional regulatory factors.