Figure 4

Model for the role of XPD as a molecular dispatcher directing CAK localization according to the cellular requirements for transcription, DNA repair and mitotic progression. During transcription and repair XPD is tightly associated with the TFIIH complex and recruits the CAK complex, which is necessary for the phosphorylation of different substrates such as nuclear receptors (NR), transcription factors (TF), the C-terminal domain of RNA Pol II (Pol II-CTD) as well as proteins involved in the DNA damage responses including p53. During the cell cycle XPD levels seem to fluctuate in some cell types. At prometaphase reduced levels of XPD (or altered affinities) allow the release of CAK from the core TFIIH complex (cTFIIH). Free CAK promotes mitotic entry by facilitating phosphorylation of the T-loop of the mitotic kinase CDK1, which is necessary for the formation of functional Cyclin-CDK complexes. Mitotic exit can occur only upon downregulation of mitotic cyclins, which may require prior dephosphorylation of the CDK1 T-loop. During exit from mitosis and interphase or during DNA-damage induced cell cycle arrest, high levels of XPD may prevent persistent activation of the mitotic kinase by relocating CAK away from its mitotic substrates.