Abstract
The NSD2 (nuclear receptor binding SET [Suppressor of variegation 3-9, Enhancer of zeste, and Trithorax] domain protein 2) gene encodes a short isoform, REIIBP (interleukin-5 response element II binding protein), via alternative transcription initiation. It is particularly overexpressed in t(4;14)+ multiple myeloma. However, the biological functions of REIIBP remain elusive. Here, we show that REIIBP localizes at the dense fibrillar component of the nucleolus. The disordered regions of REIIBP recognize pre-rRNA, which mediates the nucleolar localization of REIIBP. Proteomic analyses reveal that REIIBP is associated with many pre-rRNA processing factors and mediates lysine methylation on a set of pre-rRNA processing factors. Moreover, REIIBP dysregulates pre-rRNA processing, mediated by both disordered regions and the SET domain, and ultimately affects ribosome biogenesis. Collectively, these findings uncover the role of REIIBP in the regulation of ribosome biogenesis, which may drive the pathological process in multiple myeloma.