title: The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions.
abstract: Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells.
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address: genevieve.rodier@inserm.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Rodier
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Université de Montpellier, 34090 Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kirsh
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, 75005 Paris, France.
authors.forename: Martín
authors.initials: M
authors.lastname: Baraibar
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Houlès
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lacroix
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Delpech
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Université de Montpellier, 34090 Montpellier, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Hatchi
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Arnould
authors.affiliation: MGX-Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, 141 rue de la cardonille, 34094 Cedex 5 Montpellier, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Severac
authors.affiliation: MGX-Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, 141 rue de la cardonille, 34094 Cedex 5 Montpellier, France.
authors.forename: Emeric
authors.initials: E
authors.lastname: Dubois
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Université de Montpellier, 34090 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Caramel
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Julien
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, 75005 Paris, France; INSERM U1164, 75005 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address: laurent.lecam@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Cam
authors.affiliation: Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address: claude.sardet@inserm.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Sardet
mesh_terms: D000818:Animals; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D011743:Pyrimidines / Q000096:biosynthesis; D012097:Repressor Proteins; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D011743:Pyrimidines; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C084953:E4f1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C030986:pyrimidine