Direct targeting and regulation of RNA polymerase II by cell signaling kinases

  • Science. 2025 Nov 6;390(6773):eads7152. doi: 10.1126/science.ads7152.
Preeti Dabas  1 ,  Meritxell B Cutrona  #  1 ,  Wojciech Rosikiewicz  #  2 ,  Ryan P Kempen  1 ,  Patrick Rodrigues  3 ,  John Bowling  1 ,  Mollie S Prater  4 ,  Walter H Lang  1 ,  Adithi Danda  1 ,  Zhi Yuan  1 ,  Beisi Xu  2 ,  Shondra M Pruett-Miller  4 ,  Gang Wu  2 ,  Taosheng Chen  1 ,  Aseem Z Ansari  1
Affiliations
  • 1. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2. Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3. Hartwell Center, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4. Center for Advanced Genomic Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • # Contributed equally.
PMID: 41197002 DOI: 10.1126/science.ads7152
Abstract

Distinct phosphorylation marks are placed on the carboxyl-terminal domain (CTD) of RNA polymerase II (Pol II) during different stages of gene transcription. These phospho-CTD marks function as a molecular recognition code for the recruitment of stage-specific effector proteins. Querying ~80% of the human kinome, we identified 117 kinases that phosphorylate the CTD with a high degree of positional selectivity. The unifying characteristic linking these diverse kinases is that they selectively regulate Pol II at signal-responsive genes. An example of such "direct-at-gene" Pol II regulation is displayed by epidermal growth factor receptor (EGFR), a cell surface receptor tyrosine kinase. More broadly, our atlas of CTD kinases implicates Pol II as a direct regulatory end point for signal-transducing kinases that govern cellular physiology and contribute to the etiology of numerous diseases.

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