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

publicationsDesantis 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 G, Fanciulli M; Cell Death Dis. 2015 May 21;6:e1764. doi: 10.1038/cddis.2015.117.

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.

 

Pubmed

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