# Investigating the role of DDX3 in regulating RNA structure and mRNA export

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $38,682

## Abstract

PROJECT SUMMARY/ABSTRACT
 Mutations in DDX3X are associated with autism spectrum disorder, brain malformations, and epilepsy,
and account for up to 3% of cases of females with unexplained intellectual disability. However, little is currently
known about the molecular mechanism linking DDX3X mutations to neurodevelopmental disease. DDX3X
encodes an RNA helicase of the DEAD-box protein family and has been implicated in many aspects of RNA
metabolism, yet we still lack a mechanistic understanding of DDX3X’s role in these processes, as well as how
patient mutations in DDX3X affect RNA metabolism.
 To address this gap in knowledge of understanding of how DDX3X mutations perturb cellular function
and contribute to neurodevelopmental disease, we will investigate the mechanism of how DDX3X regulates its
target transcripts both at the level of translation initiation and mRNA nuclear export, and study how pathogenic
mutations in DDX3X alter these processes. DDX3X is implicated in translation initiation as it binds to 5’UTRs of
mRNAs, and is required for the efficient translation of a subset of mRNAs with structured 5’UTRs. However, we
still do not know the mechanism of how DDX3X can regulate the translation of these mRNAs. In addition to its
role in translation, DDX3X has been implicated in nuclear mRNA processing, and our preliminary data show
that the genes in the mRNA export pathway are genetic interaction partners of DDX3X. However, we still do
not understand what the function of DDX3X is in the nucleus or mRNA export. We hypothesize that DDX3X
regulates its target transcripts through both unwinding secondary structures in their 5’UTRs and chaperoning
their nuclear export.
 To answer this hypothesis, in our first aim we will determine how DDX3X impacts mRNA transcript
structure and ribosome engagement by measuring RNA secondary structure through in vivo structure-specific
chemical modification and high-throughput sequencing. In our second aim, we will determine the function of
DDX3X in the nucleus by examining nuclear export of DDX3X -sensitive mRNAs using RNA FISH staining.
Upon successful completion of the proposed experiments, we will have gained a greater understanding the
precise mechanism of how DDX3X regulates RNA metabolism both at the level of translation initiation as well
as mRNA export. This knowledge is critical for advancing our knowledge of RNA metabolism, as well as
understanding and developing treatments for patients with DDX3X syndrome.

## Key facts

- **NIH application ID:** 10536500
- **Project number:** 1F30HD110250-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Albert Y Xu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,682
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536500

## Citation

> US National Institutes of Health, RePORTER application 10536500, Investigating the role of DDX3 in regulating RNA structure and mRNA export (1F30HD110250-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536500. Licensed CC0.

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