+ abstract = {Fine-tuned regulation of RNA polymerase II (Pol II) activity is essential for accurate gene expression. A key layer of this regulation involves phosphorylation of Pol II{\textquoteright}s C-terminal domain (CTD), a repetitive heptapeptide tail that coordinates transcription and RNA-processing factors. The kinase P-TEFb plays a major role in this process, yet its precise phosphorylation mechanism remains unclear. Previous in vitro studies have suggested a distributive mode of action based largely on qualitative inspection of mass spectrometry data rather than quantitative analysis. Here, we use mathematical modeling of CTD phosphorylation to explore whether local context, such as neighboring phosphorylations or directional biases, affects PTEFb activity on the CTD. Our results indicate that P-TEFb acts distributively but with pronounced local cooperativity: repeats adjacent to phosphorylated sites are modified at higher rates. We find no evidence for directional bias, although the limited positional resolution of the data precludes a definitive conclusion. These results identify local context as an important factor in P-TEFb-mediated CTD phosphorylation and establish a quantitative modeling framework for dissecting multi-site modification dynamics.Competing Interest StatementThe authors have declared no competing interest.Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, EXC 2047-390685813, EXC 2151-390873048European Research Council, GA number 101126146, Advanced Grant NalpACTUniversity of Bonn, https://ror.org/041nas322, Schlegel Professorship of Jan Hasenauer},
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