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Lookup NU author(s): Dr Alex Blain
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 The Author(s). DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
Author(s): Gong C, Krupka JA, Gao J, Grigoropoulos NF, Giotopoulos G, Asby R, Screen M, Usheva Z, Cucco F, Barrans S, Painter D, Zaini NBM, Haupl B, Bornelov S, Ruiz De Los Mozos I, Meng W, Zhou P, Blain AE, Forde S, Matthews J, Khim Tan MG, Burke GAA, Sze SK, Beer P, Burton C, Campbell P, Rand V, Turner SD, Ule J, Roman E, Tooze R, Oellerich T, Huntly BJ, Turner M, Du M-Q, Samarajiwa SA, Hodson DJ
Publication type: Article
Publication status: Published
Journal: Molecular Cell
Year: 2021
Volume: 81
Issue: 19
Pages: 4059-4075.e11
Print publication date: 07/10/2021
Online publication date: 25/08/2021
Acceptance date: 28/07/2021
Date deposited: 25/08/2023
ISSN (print): 1097-2765
ISSN (electronic): 1097-4164
Publisher: Cell Press
URL: https://doi.org/10.1016/j.molcel.2021.07.041
DOI: 10.1016/j.molcel.2021.07.041
PubMed id: 34437837
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