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@ARTICLE{Jethwa:136739,
      author       = {A. Jethwa$^*$ and M. Słabicki$^*$ and J. Hüllein$^*$ and
                      M. Jentzsch$^*$ and V. Dalal$^*$ and S. Rabe and L.
                      Wagner$^*$ and T. Walther$^*$ and W. Klapper and H.
                      Bohnenberger and M. Rettel and J. Lu and A. H. Smits and F.
                      Stein and M. M. Savitski and W. Huber and Y. Aylon and M.
                      Oren and T. Zenz$^*$},
      collaboration = {M. N. Project},
      title        = {{TRRAP} is essential for regulating the accumulation of
                      mutant and wild-type p53 in lymphoma.},
      journal      = {Blood},
      volume       = {131},
      number       = {25},
      issn         = {1528-0020},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {DKFZ-2018-01177},
      pages        = {2789 - 2802},
      year         = {2018},
      abstract     = {Tumors accumulate high levels of mutant p53 (mutp53), which
                      contributes to mutp53 gain-of-function properties. The
                      mechanisms that underlie such excessive accumulation are not
                      fully understood. To discover regulators of mutp53 protein
                      accumulation, we performed a large-scale RNA interference
                      screen in a Burkitt lymphoma cell line model. We identified
                      transformation/transcription domain-associated protein
                      (TRRAP), a constituent of several histone acetyltransferase
                      complexes, as a critical positive regulator of both mutp53
                      and wild-type p53 levels. TRRAP silencing attenuated p53
                      accumulation in lymphoma and colon cancer models, whereas
                      TRRAP overexpression increased mutp53 levels, suggesting a
                      role for TRRAP across cancer entities and p53 mutations.
                      Through clustered regularly interspaced short palindromic
                      repeats (CRISPR)-Cas9 screening, we identified a
                      109-amino-acid region in the N-terminal HEAT repeat region
                      of TRRAP that was crucial for mutp53 stabilization and cell
                      proliferation. Mass spectrometric analysis of the mutp53
                      interactome indicated that TRRAP silencing caused
                      degradation of mutp53 via the MDM2-proteasome axis. This
                      suggests that TRRAP is vital for maintaining mutp53 levels
                      by shielding it against the natural p53 degradation
                      machinery. To identify drugs that alleviated p53
                      accumulation similarly to TRRAP silencing, we performed a
                      small-molecule drug screen and found that inhibition of
                      histone deacetylases (HDACs), specifically HDAC1/2/3,
                      decreased p53 levels to a comparable extent. In summary,
                      here we identify TRRAP as a key regulator of p53 levels and
                      link acetylation-modifying complexes to p53 protein
                      stability. Our findings may provide clues for therapeutic
                      targeting of mutp53 in lymphoma and other cancers.},
      cin          = {G250 / G100},
      ddc          = {610},
      cid          = {I:(DE-He78)G250-20160331 / I:(DE-He78)G100-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29653964},
      doi          = {10.1182/blood-2017-09-806679},
      url          = {https://inrepo02.dkfz.de/record/136739},
}