UCSF

DDX3X encodes for a DEAD-box RNA helicase that promotes translation of mRNAs that contain long, highly structured 5′ UTRs. DDX3X interacts with translation initiation factors and can remodel mRNA structures or RNA protein complexes in an ATP dependent manner. Our prior work found that DDX3X depletion leads to changes in translation and RNA levels while missense variants selectively impact translation, implicating DDX3X in regulating mRNA stability. Despite being an essential gene and implicated in several human cancers and developmental diseases including intellectual disability and autism spectrum disorder, the mechanisms of DDX3X in post-transcriptional gene regulation and mRNA metabolism remains poorly understood.

To address this gap in knowledge in DDX3X function in post-transcriptional gene regulation and mRNA metabolism, this work studied the mechanism of how DDX3X regulates specific mRNA transcripts and confers stability or loss of stability and how this process is altered with loss of DDX3X. DDX3X’s function in translation is well characterized, is known to be involved in nuclear export of specific mRNA, and our preliminary data demonstrates that DDX3X specific transcripts have altered stability. However, what features and characteristics of these DDX3X- dependent transcripts are key for DDX3X driven stability remain unknown. This study aimed to define what features of mRNA transcripts are key for how DDX3X regulates RNA metabolism both at the level of translation and transcript stability. This knowledge is critical for advancing our knowledge in post-transcriptional gene regulation and mRNA metabolism.