Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53 Academic Article uri icon

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abstract

  • The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.

authors

  • Desantis, A
  • Bruno, T
  • Catena, V
  • De Nicola, F
  • Goeman, F
  • Iezzi, S
  • Sorino, C
  • Gentileschi, MP
  • Germoni, S
  • Monteleone, V
  • Pellegrino, M
  • Kann, M
  • De Meo, PD
  • Pallocca, M
  • Höpker, K
  • Moretti, F
  • Mattei, E
  • Reinhardt, HC
  • Floridi, A
  • Passananti, C
  • Benzing, T
  • Blandino, Giovanni
  • Fanciulli, M

publication date

  • May 2015

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