RNA Modifications Driving Oncogenesis (RNAMoDO; U01 Clinical Trial Not Allowed)

The overarching objective of this concept is to promote mechanistic research in the emerging area of RNA modifications that drive oncogenesis, with a focus on the central role of RNA modifications in translational reprogramming of cancer cells. RNA modifications have been recognized to exert a substantial impact on gene expression and function and their de-regulation has been linked to the cancer phenotype. In particular, recent insights point to a crucial role for mRNA, tRNA, and rRNA modifications in translational reprogramming during tumor initiation, progression, and adaptation to therapy. However, the molecular mechanisms underlying this reshaping of the translatome caused by dynamic changes in RNA modifications, and especially the interplay between different RNA modifications within and across RNA molecules during translation, are not understood and represent the focus of this initiative. Historically, the research community has largely pursued investigations of RNA modifications by studying single RNA species and modification types. However, elucidating how dysregulation of mRNA, tRNA, and rRNA modifications reprograms translation to drive oncogenesis is not likely feasible for any single research lab, but will require the combination of expertise in mRNA, tRNA and rRNA biology, translational regulation, and cancer research. To stimulate progress in this emerging field, the RNAMoDO program will support collaborative research projects, preferably using an MPI structure, on how modifications in mRNA, tRNA, and rRNA molecules can drive the oncogenic process through translational reprogramming. To be responsive to the NOFO, each project will also explore the impact of interactions between modifications residing on the same or different RNA molecules during translation.