DEK-rRNA interactions regulate ribosome biogenesis and stress response

DNA/chromatin-based functions of the DEK oncogene, a unique nucleic acid-interacting factor in metazoans, have been widely investigated, yet its role in cellular RNA biology is under-studied. Herein we employed CLIP-seq alongside mutational, biochemical, and cellular approaches to gain deeper insights into the cellular DEK-RNA interplay. We confirm interaction of DEK with coding RNA, yet also report association with ribosomal RNA (rRNA) and thereby establishing a robust link between DEK and ribosome biology. Indeed, cells lacking DEK showed marked deficits in cytoplasmic ribosome quality and function. This phenotype was exclusively rescued by C-terminal DEK, harboring two RNA interaction domains, but not by an rRNA-binding deficient mutant. Mechanistically, we uncovered pleiotropic involvement of DEK in RNA polymerase I-mediated rRNA transcription and processing pathways. More specifically, we found direct interaction of DEK with RNA polymerase III-transcribed 5S rRNA and identified DEK as a regulator of the Impaired Ribosome Biogenesis Checkpoint (IRBC). Within this ribosomal stress pathway, DEK depletion results in free 5S RNP, triggering stabilization of p53 via inhibition of MDM2. In summary, our multilayer analysis revealed DEK as a potent cellular RNA binding protein and provides first evidence of DEK as a regulator of ribosome biogenesis and stress response via the 5S RNP-MDM2-p53 axis.