Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.molcel.2021.07.041

Type

Journal article

Journal

Molecular cell

Publication Date

10/2021

Volume

81

Pages

4059 - 4075.e11

Addresses

Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK.

Keywords

B-Lymphocytes, Cell Line, Tumor, Animals, Mice, Transgenic, Humans, Lymphoma, B-Cell, Proto-Oncogene Proteins c-myc, Neoplasm Proteins, Proteome, Minor Histocompatibility Antigens, Protein Biosynthesis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Child, Child, Preschool, Female, Male, DEAD-box RNA Helicases, Young Adult, Endoplasmic Reticulum Stress, Loss of Function Mutation, Proteostasis