@article{MaudetSourisceDraginetal.2013,
  author    = {Maudet, Claire and Sourisce, Ad{\`e}le and Dragin, Lo{\"i}c and Lahouassa, Hichem and Rain, Jean-Christopher and Bouaziz, Serge and Ramirez, Bertha C{\´e}cilia and Margottin-Goguet, Florence},
  title     = {HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP},
  series = {PLOS ONE},
  volume    = {8},
  journal   = {PLOS ONE},
  number    = {10},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0077320},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128316},
  pages     = {e77320},
  year      = {2013},
  abstract  = {The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered.},
  language  = {en}
}
@article{SchlerethHeylKrampitzetal.2013,
  author    = {Schlereth, Katharina and Heyl, Charlotte and Krampitz, Anna-Maria and Mernberger, Marco and Finkernagel, Florian and Scharfe, Maren and Jarek, Michael and Leich, Ellen and Rosenwald, Andreas and Stiewe, Thorsten},
  title     = {Characterization of the p53 Cistrome - DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions},
  series = {PLOS Genetics},
  volume    = {9},
  journal   = {PLOS Genetics},
  number    = {8},
  issn      = {1553-7404},
  doi       = {10.1371/journal.pgen.1003726},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127579},
  pages     = {e1003726},
  year      = {2013},
  abstract  = {p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context-and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing.},
  language  = {en}
}
@article{TimofeevSchlerethWanzeletal.2013,
  author    = {Timofeev, Oleg and Schlereth, Katharina and Wanzel, Michael and Braun, Attila and Nieswandt, Bernhard and Pagenstecher, Axel and Rosenwald, Andreas and Els{\"a}sser, Hans-Peter and Stiewe, Thorsten},
  title     = {p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo},
  series = {Cell Reports},
  volume    = {3},
  journal   = {Cell Reports},
  doi       = {10.1016/j.celrep.2013.04.008},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122168},
  pages     = {1512-1525},
  year      = {2013},
  abstract  = {Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer.},
  language  = {en}
}