title: Essential role for centromeric factors following p53 loss and oncogenic transformation.
abstract: In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within theHjurpandCenpapromoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre-established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an "epigenetic addiction" to the HJURP chaperone represents an Achilles' heel in p53-deficient transformed cells.
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Dan
authors.initials: D
authors.lastname: Filipescu
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Naughtin
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Katrina
authors.initials: K
authors.lastname: Podsypanina
authors.affiliation: Institut Curie, PSL Research University, UMR3244, CNRS, Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, UPMC Université Paris 06, UMR3244, CNRS, F-75005 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lejour
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Gurard-Levin
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Orsi
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Iva
authors.initials: I
authors.lastname: Simeonova
authors.affiliation: Institut Curie, PSL Research University, UMR3244, CNRS, Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, UPMC Université Paris 06, UMR3244, CNRS, F-75005 Paris, France.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Toufektchan
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
authors.affiliation: Institut Curie, PSL Research University, UMR3244, CNRS, Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, UPMC Université Paris 06, UMR3244, CNRS, F-75005 Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Toledo
authors.affiliation: Institut Curie, Paris Sciences et Lettres (PSL) Research University, UMR3664, Centre Nationnal de la Recherche Scientifique (CNRS), Equipe Labellisée Ligue contre le Cancer, F-75005 Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Université Paris 06, UMR3664, CNRS, F-75005 Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Almouzni
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism*; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009857:Oncogenes / Q000235:genetics*
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; C000619701:Cenpa protein, mouse; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C524371:HJURP protein, human
keywords: CENP-A; HJURP; centromere; oncogenic transformation; p53