title: Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.
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.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Desantis
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Bruno
authors.affiliation: 1] Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy [2] Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio Coppito 2, L'Aquila, 67100, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Catena
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Nicola
authors.affiliation: Oncogenomic Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Goeman
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iezzi
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sorino
authors.affiliation: SAFU, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Gentileschi
authors.affiliation: SAFU, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Germoni
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, Rome, 00144, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Monteleone
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, Rome, 00144, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kann
authors.affiliation: HPC CINECA, Via dei Tizii, 6, Rome, 00185, Italy.
authors.forename: P D
authors.initials: PD
authors.lastname: De Meo
authors.affiliation: Oncogenomic Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pallocca
authors.affiliation: Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Höpker
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, Rome, 00144, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Moretti
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, Rome, 00144, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mattei
authors.affiliation: 1] Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: H C
authors.initials: HC
authors.lastname: Reinhardt
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Floridi
authors.affiliation: IBMN-CNR, Department of Molecular Medicine, "Sapienza" University, Viale Regina Elena 291, Rome, 00161, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Passananti
authors.affiliation: 1] Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany [3] Systems Biology of Aging, University of Cologne, Cologne, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Oncogenomic Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Blandino
authors.affiliation: 1] Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy [2] SAFU, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fanciulli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D060168:Thymocytes / Q000473:pathology / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53