Ddx21, a member of the DEAD-box RNA helicase family, is pivotal in RNA metabolism, participating in ribosomal RNA (rRNA) processing, transcription, and translation. It is involved in various biological processes such as mRNA transcription, alternative splicing, and is associated with pathways related to tissue differentiation, ribosome biogenesis, and genome stability. Its functions are crucial for normal cellular activities and its dysregulation may lead to diseases like cancer [1,2,3,5,8].

Glucose binds to the ATP-binding domain of Ddx21, altering its conformation, inhibiting helicase activity, and dissociating Ddx21 dimers. This glucose-induced change promotes the splicing of pro-differentiation genes during epidermal differentiation [1]. Ddx21 interacts with METTL3 for co-recruitment to chromatin via R-loops recognition, facilitating m6A deposition on nascent RNA at transcription termination regions, thus promoting transcription termination and genome stability [2]. SLERT lncRNA interacts with Ddx21, loosening Ddx21-formed rings around Pol I complexes and relieving the suppression on pre-rRNA transcription [3]. In colorectal cancer, phase-separated Ddx21 binds to the MCM5 gene locus, activating the EMT pathway and promoting metastasis [4]. Ddx21 also coordinates multiple steps of ribosome biogenesis, promoting rRNA transcription, processing, and modification in the nucleolus, and facilitating P-TEFb release from 7SK snRNP in the nucleoplasm to promote transcription of target genes [5]. In breast cancer cells, PARP-1 activation by snoRNAs leads to DDX21 ADP-ribosylation, which is essential for its nucleolar localization and promotion of rDNA transcription [6]. In acute myeloid leukaemia, super-enhancer-driven IGF2BP2 and IGF2BP3 upregulate Ddx21 in an m6A-dependent manner, and Ddx21 promotes cell proliferation by recruiting YBX1 to trigger ULK1 expression [7].

In summary, Ddx21 is essential for RNA-related biological processes, with its function being modulated by various factors. Studies, some potentially involving gene knockout models, have revealed its significance in tissue differentiation, cancer progression, and ribosome biogenesis. Understanding Ddx21's function provides insights into disease mechanisms and may offer potential therapeutic targets for related diseases [1,2,3,4,5,6,7,8].