Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

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Authors

GONG C. KRUPKA J.A. GAO J. GRIGOROPOULOS N.F. GIOTOPOULOS G. ASBY R. SCREEN M. USHEVA Z. CUCCO F. BARRANS S. PAINTER D. ZAINI N.B.M. HAUPL B. BORNELOV S. DE LOS MOZOS I.R. MENG W. ZHOU P.X. BLAIN A.E. FORDE S. MATTHEWS J. TAN M.G.K. BURKE G.A.A. SZE S.K. BEER P. BURTON C. CAMPBELL P. RAND V. TURNER Suzanne Dawn ULE J. ROMAN E. TOOZE R. OELLERICH T. HUNTLY B.J. TURNER M. DU M.Q. SAMARAJIWA S.A. HODSON D.J.

Year of publication 2021
Type Article in Periodical
Magazine / Source Molecular Cell
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.sciencedirect.com/science/article/pii/S1097276521006250?via%3Dihub
Doi http://dx.doi.org/10.1016/j.molcel.2021.07.041
Keywords AZFA GENE DDX3Y; MESSENGER-RNA; TUMOR-SUPPRESSOR; STRESS GRANULES; READ ALIGNMENT; EEF2 KINASE; TRANSLATION; PROTEIN; MUTATIONS; IDENTIFICATIONAZFA GENE DDX3Y; MESSENGER-RNA; TUMOR-SUPPRESSOR
Description 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.

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