In conclusion, although the molecular events linking the inactivation of hDIS3 nucleolytic properties and its inability to efficiently degrade transcripts with reduced cell viability remain to be elucidated, the negative synthetic interaction between MM-associated RNB domain mutations and PIN domain dysfunction may suggest the latter as a promising drug target for cancers bearing mutations that affect hDIS3 RNB domain exonucleolytic activity. This evidence concerns the gene DYNLL1 and cancer.