The PUF RNA-binding protein, FBF-2, maintains stem cells without binding to RNA.

Like all canonical PUF proteins, Caenorhabditis elegans FBF-2 binds to specific RNAs via tripartite recognition motifs. Here, we report that an FBF-2 mutant protein that cannot bind to RNA is nonetheless biologically active and maintains stem cells. This unexpected result challenges the conventional wisdom that RBPs must bind to RNAs to achieve biological activity. Also unexpectedly, FBF-2 interactions with partner proteins can compensate for the loss of RNA binding. FBF-2 only loses biological activity when its RNA-binding and partner interactions are both defective. These findings highlight the complementary contributions of RNA-binding and protein partner interactions to the activity of an RNA-binding protein.