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

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

doi:http://dx.doi.org/10.1101/gad.314286.118

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

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Aubrey BJ, Janic A, Chen Y, Chang C, Lieschke EC, Diepstraten ST, et al. Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development. Genes and Development. 2018 Nov 1;32(21-22):1420–9. DOI: 10.1101/gad.314286.118

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.