The WD40-repeat domain protein Wdr68/Dcaf7 is essential during embryonic development for craniofacial patterning and functions as a molecular scaffold to organize the activity of multiple kinases. Dual-specificity Tyrosine-regulated Kinase 1A (Dyrk1a) physically interacts with Wdr68, is overexpressed in Down’s Syndrome patients, and is essential for embryonic development. Dyrk1a acts as a nuclear-localized RNApII CTD-kinase to activate the expression of downstream target genes. Thus, Wdr68 might act during development by facilitating the kinase functions of Dyrk1a with impacts on downstream gene expression. Here we found that a Gal4DBD-Wdr68 fusion protein minimally (2-fold) activated a 5xGal4-Luciferase reporter in transiently transfected mouse C2C12 cells maintained in growth medium (GM). In contrast, the Gal4DBD-Wdr68 fusion activated the 5xGal4-Luc reporter 18-fold when cells were maintained in differentiation medium (DM). Western blot analysis revealed strong up-regulation of endogenous Wdr68 and Dyrk1a protein levels in cells maintained in DM versus GM suggesting that the increased levels of Dyrk1a CTD-kinase activity might underlie the mechanism of Gal4DBD-Wdr68 activity. To further analyze the relationship between Wdr68 and Dyrk1a, we then generated Wdr68 deletions by CRISPR/Cas9 gene targeting in C2C12 cells. We found near-complete loss of Dyrk1a protein expression in Wdr68 deletion sublines relative to a non-target (NT1) control subline. We also detected smaller fragments of the closely related kinase Dyrk1b suggesting a general role for Wdr68 in the stabilization of its interaction partners. Wdr68/Dcaf7 is an interaction partner for the DDB1-Cul4a complex and therefore may play a role in Ubiquitin-mediated protein turnover. To explore the mechanism behind the loss of Dyrk1a expression, we treated the Wdr68 deletion sublines and NT1 controls with the proteasome inhibitor LLNL. We found that 6 hours of 50uM LLNL treatment could restore near-normal expression levels of full-length Dyrk1a in the Wdr68 deletion sublines. We also generated Dyrk1a deletions by CRISPR/Cas9 gene targeting in C2C12 cells and found near normal levels of Wdr68 expression in them suggesting the stabilization is unidirectional as Wdr68àDyrk1a. Thus, Wdr68 is required for stabilization of Dyrk1 kinases and may represent a novel therapeutic target for the modulation of Dyrk1a activity.