Landmark Study Reveals Unexpected Kinase Network Controlling Gene Transcription,Offering New cancer Insights
A groundbreaking new study published today in Science dramatically expands our understanding of how genes are transcribed,revealing a complex network of kinases that directly regulate the process and offering potential new avenues for cancer treatment. Researchers at St. Jude Children’s Research Hospital have identified 117 kinases capable of modifying RNA polymerase II,the enzyme responsible for converting genes into messenger RNA,substantially increasing the known number of kinases involved in this crucial cellular function.
The process of gene transcription is meticulously controlled by modifications – specifically, phosphorylation patterns – to the “tail” of RNA polymerase II. For years, scientists have understood the role of a limited number of kinases in this process. However, this research demonstrates a far more intricate system than previously imagined.
Researchers sought to clarify the role of kinases beyond the traditionally recognized ones. “We knew there were kinases beyond the canonical ones, but appreciated that specificity often comes from proximity,” a senior researcher explained.
The study’s most surprising finding centers on the ability of a receptor kinase – specifically, EGFR – to directly phosphorylate RNA polymerase II within the nucleus. This challenges the conventional understanding of cell signaling as a linear relay race. “the most unlikely idea was that a cell surface receptor kinase such as EGFR coudl phosphorylate RNA polymerase II,” a lead scientist stated. “To my surprise, our imaging data showed the receptor in the nucleus, somthing wich has been reported for decades, but marginalized. Our evidence confirmed this, and now we can finally explain why.”
Exhaustive experimentation confirmed that phosphorylation of RNA polymerase II at position one by EGFR is essential for transcription. This suggests a more immediate and integrated form of cell signaling.”People think of cell signaling as a relay of kinases that than act on a transcription factor, but our data tells us it’s more integrated than that,” the researcher continued. “Signaling can be more immediate, as signaling kinases are not waiting for transcription factors to find their home. Thay can get to the site and control the process more directly.”
Implications for Cancer Therapy
The findings have meaningful implications for understanding and treating cancer. The study establishes a clear link between phosphorylation of the RNA polymerase II tail and disease development. “Some aggressive cancers have kinases untethered in the nucleus, disrupting transcriptional programs,” a researcher 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 were we perceive the therapeutic vulnerability,this changes how we think about pathology.”
EGFR, prominently mutated in lung cancer, is a key example. the ability of EGFR to directly influence transcription within the nucleus suggests new targets for therapeutic intervention. .
The study’s first author is Preeti Dabas, St. Jude. Co-second authors are Meritxell Cutrona and Wojciech Rosikiewicz, also of St.Jude. Additional authors include Ryan Kempen, Patrick Rodrigues, John Bowling, Mollie Prater, Walter Lang, Adithi Danda, Zhi Yuan, Beisi Xu, Shondra Pruett-Miller, Gang Wu and Taosheng Chen, all from St. Jude.
the research was supported by the National Cancer Institute (P30 CA021765) and the American Lebanese Syrian Associated Charities (ALSAC).
Source: St. Jude Children’s Research Hospital. journal reference: Dabas, P., et al. (2025).Direct targeting and regulation of RNA polymerase II by cell signaling kinases. Science. doi: 10.1126/science.ads7152. https://www.science.org/doi/10.1126/science.ads7152.
