DDX21 is a DEAD-box RNA helicase that serves as a multifunctional regulator of gene expression and genome stability. The protein primarily functions in ribosome biogenesis by binding various RNAs including rRNAs and snoRNAs, promoting rRNA transcription and processing in the nucleolus 1. DDX21 forms ring-shaped structures around RNA polymerase I complexes, with its activity modulated by the lncRNA SLERT, which loosens these rings to enhance pre-rRNA transcription 12. Beyond ribosomal function, DDX21 acts as a sensor of RNA polymerase II transcription by binding 7SK RNA and facilitating P-TEFb release to promote transcription. The helicase undergoes glucose-dependent conformational changes that dissociate DDX21 dimers, leading to nucleoplasmic relocalization where it regulates mRNA splicing of differentiation genes 3. DDX21 also maintains genome stability through multiple mechanisms: it resolves R-loops in collaboration with ADAR1 and other helicases during replication stress 4, mediates co-transcriptional m6A modification through METTL3 interaction 5, and undergoes phase separation to regulate cancer metastasis pathways 6. These diverse functions establish DDX21 as a critical coordinator of transcription, RNA processing, and genome integrity 78.