DDX21 is a DEAD-box RNA helicase that controls the transcriptional status of RNA polymerase I and II. In the nucleolus, DDX21 broadly and specifically localizes rDNA loci, binding to the transcribed region of rRNA but not to intergenic spacers. Besides, it binds various other types of RNAs such as snoRNAs, 7SK and mRNAs, even though to a lower extent (Calo et al. 2015). Indeed, it promotes rRNA transcription, modification and processing, being, moreover, required for rRNA-2’-O-methylation. Concerning this, it is probably involved in the recruitment of snoRNAs SNORD56 and SNORD58 with pre-ribosomal complexes (Calo et al. 2015, Sloan et al. 2015). It participates in transcription regulation cleaving P-TEFb from 7SK snRNP so that this release is dependent on its helicase activity. Therefore, it promotes the transcription of its own target genes (Calo et al. 2015). It is also involved in the maintenance of DNA homeostasis, preventing damage to R-loops and trascription-associated genomic instability. Indeed, deacetylation by SIRT7 activates the helicase activity, thereby overcoming R-loop-mediated stalling of RNA polymerases (Song et al. 2017).