A study published in PNAS Nexus reveals that the oncogenic protein EWS::FLI1, which drives Ewing sarcoma, maintains its capacity to activate normally silenced repetitive DNA regions in yeast but largely loses its ability to alter gene expression on a global scale. This distinction suggests that both functions depend on different molecular mechanisms.
Ewing sarcoma is an aggressive cancer primarily affecting adolescents and young adults, with the abnormal EWS::FLI1 protein being the driver in most cases. The research team, in collaboration with the Pediatric Cancer Center Barcelona at the Hospital Sant Joan de Déu, simplified the cellular system using yeast to separately analyze the activation of specific DNA regions and the global reprogramming of gene expression.
According to Dr. Cayetano González, Emeritus Professor at IRB Barcelona and co-leader of the work, studying simpler organisms allows for a piece-by-piece deconstruction of the mechanism, eliminating factors present in animal cells and helping to distinguish between oncogenic activities requiring evolutionarily conserved components and those of more recent evolution.
In yeast, EWS::FLI1 was able to bind to hundreds of genomic sites and redistribute the transcription machinery (RNA polymerase II), but these changes had minimal impact on gene expression. However, when GGAA repetitive sequences were introduced, the protein reversed the silencing of an adjacent gene, demonstrating its ability to activate these regions even in a very different cellular environment.
Dr. Diego Velázquez, co-first author of the study, highlights that the ability to activate GGAA sequences may rely on basic cellular mechanisms, while gene reprogramming appears to require components more specific to animal cells. This yeast model opens the door to genetic screens to identify the cellular components necessary for each protein activity.
The research, which also involved Dr. Cristina Molnar, Dr. Jose Reina, and Dr. Jaume Mora, received funding from the European Regional Development Fund, the Ministry of Science and Innovation, the State Research Agency, and the Fundació Sant Joan de Déu per la Recerca.
