DND1-NANOS3 shapes the PGC transcriptome via a heptanucleotide sequence in mRNA 3' UTRs.

Abstract

Primordial germ-cell survival requires joint function of the RNA-binding proteins (RBPs) DND1 and NANOS3, yet how they collaborate has not been established. Here, we discover a paradigm of "two-factor authorization," where RBPs 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. RBPs 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.