The Role of the RNA Helicase DDX3X in Medulloblastoma Progression

Abstract

Medulloblastoma is the most common pediatric brain cancer, with about five cases per million in the pediatric population. Current treatment strategies have a 5-year survival rate of 70% or more but frequently lead to long-term neurocognitive defects, and recurrence is relatively high. Genomic sequencing of medulloblastoma patients has shown that DDX3X, which encodes an RNA helicase involved in the process of translation initiation, is among the most commonly mutated genes in medulloblastoma. The identified mutations are 42 single-point amino acid substitutions and are mostly not complete loss-of-function mutations. The pathological mechanism of DDX3X mutations in the causation of medulloblastoma is poorly understood, but several studies have examined their role in promoting cancer progression. This review first discusses the known roles of DDX3X and its yeast ortholog Ded1 in translation initiation, cellular stress responses, viral replication, innate immunity, inflammatory programmed cell death, Wnt signaling, and brain development. It then examines our current understanding of the oncogenic mechanism of the DDX3X mutations in medulloblastoma, including the effect of these DDX3X mutations on growth, biochemical functions, translation, and stress responses. Further research on DDX3X's mechanism and targets is required to therapeutically target DDX3X and/or its downstream effects in medulloblastoma progression.

Keywords: DDX3X; RNA helicase; medulloblastoma; translation.

Figure 2

Location of the medulloblastoma-associated mutations in DDX3X. (A) A sequence schematic of DDX3X with the helicase core in green and the N- and C-terminal regions in black. The identified mutations (orange lines) and conserved DEAD-box helicase motifs (labeled in rectangles) are marked. (B) Crystal structure of DDX3X from (PDB ID: 7LIU) [71] with medulloblastoma-associated mutations marked. Sites that were lethal in yeast Ded1 are shown in black while the rest are shown in pink [70]. An ATP analog is shown in blue, single-stranded RNA is shown in red, and magnesium ion is shown in yellow.

Figure 1

Functions of DDX3X. Schematic to demonstrate the various processes in which DDX3X is involved at the cellular and organismal level. These processes include translation initiation [20,21,22,23,24,25,26,27,28,29,30], stress response [23,28,31,32,33,34,35,36,37,38,39,40], pre-mRNA splicing [20,41], viral replication [42,43,44,45,46,47,48], innate immunity [49,50,51,52,53,54,55], Wnt signaling [10,56], apoptosis [57,58] and brain formation [59,60,61,62,63,64,65,66,67,68,69]. Question marks indicate that the role of DDX3X in these processes requires further study.