Comment on "Direct Targeting and Regulation of RNA Polymerase II by Cell Signaling Kinases"

Dabas et al. in Science 2025 report that approximately 117 human kinases directly phosphorylate the C-terminal domain (CTD) of RNA polymerase II (Pol II), proposing an extensive, direct biochemical bridge between signal transduction and transcriptional control. Such a sweeping claim that one-fourth of the human kinome directly targets the CTD represents a profound revision of canonical transcriptional biology. However, the evidence presented relies primarily on in vitro kinase assays using short CTD peptides, sparse in-cell validation, and mechanistically incomplete models of nuclear trafficking, chromatin targeting, structural compatibility, and catalytic specificity. In this extended critique, we demonstrate that the conclusions of this study are not supported by current biochemical, structural, cell biological, or genomic data. We outline severe shortcomings in assay design, lack of quantitative kinetics, incompatibilities with known Pol II structural constraints, unsupported assumptions about nuclear localization, inappropriate extension to “direct-at-gene” mechanisms, absence of global transcriptional effects, failure to align with the essential role of canonical CDKs, and missing transparency in dataset reporting. We conclude that the central claims of the study are premature and contradicted by decades of established transcriptional research. Substantial new evidence is required before revising the mechanistic model of Pol II CTD regulation.