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Timofeev, O.* ; Koch, L.* ; Niederau, C.* ; Tscherne, A.* ; Schneikert, J.* ; Klimovich, M.* ; Elmshäuser, S.* ; Zeitlinger, M.* ; Mernberger, M.* ; Nist, A.* ; Osterburg, C.* ; Dötsch, V. ; Hrabě de Angelis, M. ; Stiewe, T.* ; German Mouse Clinic Consortium (Aguilar-Pimentel, J.A. ; Schmidt-Weber, C.B. ; Becker, L. ; Klopstock, T. ; Cho, Y.-L. ; Spielmann, N. ; Amarie, O.V. ; Garrett, L. ; Hölter, S.M. ; Wurst, W. ; Calzada-Wack, J. ; Sanz-Moreno, A. ; Klein-Rodewald, T. ; Rathkolb, B. ; Wolf, E. ; Östereicher, M.A. ; Miller, G. ; Maier, H. ; Stöger, C. ; Leuchtenberger, S. ; Gailus-Durner, V. ; Fuchs, H.)

Phosphorylation control of p53 DNA binding cooperativity balances tumorigensis and aging.

Cancer Res. 80, 5231-5244 (2020)
DOI Order publishers version
Open Access Green: Postprint online available 10/2021

Post-translational modifications are essential for regulating the transcription factor p53 which binds DNA in a highly cooperative manner to control expression of a plethora of tumor suppressive programs. Here we show at the biochemical, cellular, and organismal level that the cooperative nature of DNA binding is reduced by phosphorylation of highly conserved serine residues (human S183/S185, mouse S180) in the DNA binding domain. To explore the role of this inhibitory phosphorylation in vivo, new phosphorylation-deficient p53-S180A knock-in mice were generated. ChIP-seq and RNA-seq studies of S180A knock-in cells demonstrated enhanced DNA binding and increased target gene expression. In vivo, this translated into a tissue-specific vulnerability of the bone marrow that caused depletion of hematopoietic stem cells and impaired proper regeneration of hematopoiesis after DNA damage. Median lifespan was significantly reduced by 20% from 709 days in wild-type to only 568 days in S180A littermates. Importantly, lifespan was reduced by a loss of general fitness and increased susceptibility to age-related diseases, not by increased cancer incidence as often seen in other p53 mutant mouse models. For example, S180A knock-in mice showed markedly reduced spontaneous tumorigenesis and increased resistance to Myc-driven lymphoma and Eml4-Alk-driven lung cancer. Preventing phosphorylation of S183/S185 in human cells boosted p53 activity and allowed tumor cells to be killed more efficiently. Together out data identify p53 DNA binding domain phosphorylation as a druggable mechanism that balances tumorigenesis and aging.

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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell-cycle Arrest; Hematopoietic Stem; Tumor Suppression; Aurora Kinase; Life-span; Apoptosis; Protein; Domain; Mdm2; Acetylation
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Journal Cancer Research
Quellenangaben Volume: 80, Issue: 23, Pages: 5231-5244 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed
Grants Deutsche Jose Carreras Leukamie Stiftung e.V.
Deutsche Forschungsgemeinschaft
German Center for Lung Research (DZL)
BMBF
Behring-Rontgen Stiftung
Deutsche Krebshilfe