(MEMPHIS, Tenn. – November 6, 2025) The enzyme RNA polymerase II transcribes genes into messenger RNA. This process is guided by modifications to the enzyme's "tail" called phosphorylation patterns. Scientists at St. Jude Children's Research Hospital explored these patterns, identifying 117 kinases that could phosphorylate multiple locations within the protein tail. This greatly expands upon the set of kinases previously known to phosphorylate RNA polymerase II. The work also links the enzyme's activity to multiple diseases, including cancer, for example, through the cell-surface tyrosine kinase EGFR, which was shown to phosphorylate RNA polymerase II in the nucleus. EGFR is prominently mutated in lung cancer. The findings were published today in Science.
RNA polymerase II's tail is composed of repeats of the same seven amino acids. Cells control distinct steps of gene transcription using kinases, which attach phosphate groups onto this repeated amino acid sequence, particularly at positions two and five. The relevance of the other five amino acids to RNA polymerase II function has been debated.
Aseem Ansari , St. Jude Department of Chemical Biology & Therapeutics chair, sought to clarify this uncertainty. "We knew there were kinases beyond the canonical ones, but appreciated that specificity often comes from proximity," Ansari said. "Many kinases can phosphorylate the tail, so we wanted to sort through them to determine which are meaningful."
Cell surface kinase delivers message to the nucleus
The researchers tested 427 kinases to see if, how and where they could phosphorylate the RNA polymerase tail, with Ansari crediting the importance of the infrastructure available at St. Jude for such an undertaking. "The study would not have been possible without the incredible shared and departmental resources that are available to scientists at St. Jude," he said. They identified 117 kinases with a substantial preference for phosphorylation location. This included previously disregarded positions, as 54 of the tested 62 tyrosine kinases acted exclusively at position one.
Within this comprehensive kinase atlas were some unexpected findings relating to cell signaling. "The most unlikely idea was that a cell surface receptor kinase such as EGFR could phosphorylate RNA polymerase II," said Ansari. "To my surprise, our imaging data showed the receptor in the nucleus, something which has been reported for decades, but marginalized. Our evidence confirmed this, and now we can finally explain why."
Exhaustive experimentation confirmed that RNA polymerase II phosphorylation at position one by EGFR was required for transcription. This carries significant implications for how cell signaling is perceived.
"People think of cell signaling as a relay of kinases that then act on a transcription factor, but our data tells us it's more integrated than that," Ansari said. "Signaling can be more immediate, as signaling kinases are not waiting for transcription factors to find their home. They can get to the site and control the process more directly."
The study greatly expands on RNA polymerase II phosphorylation patterns and supports further exploration of their individual relevance. It also creates a link between phosphorylation of the enzyme's tail and diseases such as cancer.
"Some aggressive cancers have kinases untethered in the nucleus, disrupting transcriptional programs," Ansari explained. "We've been ignoring these kinases in the nucleus because it's a small fraction of the signal; the expectations were that signaling is happening at the cell surface. But by shifting where we perceive the therapeutic vulnerability, this changes how we think about pathology."
Authors and funding
The study's first author is Preeti Dabas, St. Jude. The study's co-second authors are Meritxell Cutrona and Wojciech Rosikiewicz, St. Jude. The study's other authors are Ryan Kempen, Patrick Rodrigues, John Bowling, Mollie Prater, Walter Lang, Adithi Danda, Zhi Yuan, Beisi Xu, Shondra Pruett-Miller, Gang Wu and Taosheng Chen, St. Jude.
The study was supported by the National Cancer Institute (P30 CA021765) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
