Cak1 in budding yeast is predominantly cytoplasmic, whereas Cdk7 in higher eukaryotes is largely nuclear, although it has also been reported to shuttle between nucleus and cytoplasm. Another potential explanation of the specific requirement for Csk1 is kinetically distinct TH-302 918633-87-1 activation pathways driven by the two types of CAK. In vitro, the Cdk7 and Cak1/Csk1 classes are distinguished by their substrate preferences. Human Cdk7 recognizes the mitotic CDK, Cdk1, only in a complex with cyclin, whereas Cak1 and Csk1 prefer CDK monomers. In budding yeast, the cell-cycle CDK is phosphorylated on its T-loop in vivo while in monomeric form, and throughout the cell cycle. Co-expression of S. pombe Csk1 and Cdk1 in insect cells likewise generated monomeric Cdk1 that was phosphorylated on Thr167 and could be activated by cyclin in a single step in vitro. A similar pathway operating in fission yeast could generate active CDK even in cells arrested in response to DNA damage, because the inhibitory kinases that phosphorylate Tyr15 of Cdk1��and which are terminal effectors of negative signaling by the G2 checkpoint��act preferentially on CDK/cyclin complexes. Tracing the connections between Csk1 and defined repair pathways through individual CDK intermediaries is difficult, because CAK function is pleiotropic. A case in point is the unexpected involvement of Cdk9 in the response to UV-induced damage. Bypassing the requirement for T-loop phosphorylation to activate Cdk9, in cdk9T212E mutant strains, could permit a more direct test of Cdk1��s role, but might also uncover added complexity: e.g. functions of other, as-yet-unconfirmed Csk1 targets such as Lsk1. Cdk1 requires T-loop phosphorylation for its essential function, precluding a simple, direct test of UVsensitivity in a cdc2T167A mutant. The results of our study clearly show that the SCN5A F1473C mutation, which was discovered as a de novo mutation in a newborn, clearly disrupts inactivation of Nav1.5 channels in manners which contribute to delayed repolarization in cardiac cells expressing this channel variant. The present study adds to a growing literature that suggests that LQTS mutations in general and LQT-3 mutations in particular, are both more prevalent and particularly problematic in hearts of infants compared with Carfilzomib adults. In a systematic study of autopsied SIDS cases Ackerman et al reported an incidence of SCN5A mutations of 2.1% and most recently, in a survey of SIDS victims involving 201 Norewegian cases, approximately half of the gene variants linked to LQTS were found to be SCN5A mutations, which is higher than the approximately 10% incidence reported in adult LQTS patients. Several characteristics of the clinical phenotype and therapeutic responses we report are consistent with those previously described for LQT-3 cases in infants, including both pronounced QT prolongation and mixed efficacy in the controlling QT prolongation and resulting arrhythmias with Na + channel blockers.