Mms19 is a mitotic gene permitting Cdk7 to be fully active as Cdk activating kinase

Abstract

Mms19 encodes a cytosolic iron-sulfur assembly component. We found that Drosophila Mms19 is also essential for mitotic divisions and for the proliferation of diploid cells. Reduced Mms19 activity causes severe mitotic defects in spindle dynamics and chromosome segregation, and loss of zygotic Mms19 prevents the formation of imaginal discs. The lacking mitotic tissue of Mms19P/P larvae can be rescued by over-expression of the Cdk-activating kinase (CAK), an activator of the mitotic Cdk1, suggesting that Mms19+ functions in mitosis to allow CAK to become fully active as Cdk1-activating kinase. Bound to Xpd and TFIIH, the CAK subunit Cdk7 phosphorylates transcriptional targets and not cell cycle Cdks. In contrast, free CAK (Cdk7/CyclinH/Mat1) phosphorylates and activates Cdk1. Physical and genetic interaction studies between Mms19/Mms19 and Xpd/xpd suggest that their interaction prevents Xpd from binding to the CAK complex. Xpd bound to Mms19 therefore frees CAK complexes, allowing them to phosphorylate Cdk1 and facilitating progression to metaphase. The structural basis for the competitive interaction with Xpd seems to be the binding of Mms19, core TFIIH and CAK to neighboring or overlapping regions of Xpd.