Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

Brandon J. Aubrey; Ana Janic; Yunshun Chen; Catherine Chang; Elizabeth C. Lieschke; Sarah T. Diepstraten; Andrew J. Kueh; Jonathan P. Bernardini; Grant Dewson; Lorraine A. O'Reilly; Lachlan Whitehead; Anne K. Voss; Gordon K. Smyth; Andreas Strasser; Gemma L. Kelly

doi:10.1101/gad.314286.118

Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

¹Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria 3052, Australia;
²Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria 3050, Australia;
³School of Mathematics and Statistics, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia

Corresponding authors: strasser{at}wehi.edu.au, gkelly{at}wehi.edu.au

↵5 These authors contributed equally to this work.
↵6 These authors contributed equally to this work.

↵4 Present address: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

Mutations in Trp53, prevalent in human cancer, are reported to drive tumorigenesis through dominant-negative effects (DNEs) over wild-type TRP53 function as well as neomorphic gain-of-function (GOF) activity. We show that five TRP53 mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC overexpression in a manner that distinguishes the hot spot Trp53 mutations. RNA sequencing revealed that the mutant TRP53 DNE does not globally repress wild-type TRP53 function but disproportionately impacts a subset of wild-type TRP53 target genes. Accordingly, TRP53 mutant proteins impair pathways for DNA repair, proliferation, and metabolism in premalignant cells. This reveals that, in our studies of lymphomagenesis, mutant TRP53 drives tumorigenesis primarily through the DNE, which modulates wild-type TRP53 function in a manner advantageous for neoplastic transformation.

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Footnotes

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.314286.118.

Received March 13, 2018.
Accepted September 19, 2018.

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