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Publications de l’équipe Mécanismes moléculaires de la dynamique des chromosomes Année de publication : 2013 Daniele Fachinetti, H Diego Folco, Yael Nechemia-Arbely, Luis P Valente, Kristen Nguyen, Alex J Wong, Quan Zhu, Andrew J Holland, Arshad Desai, Lars E T Jansen, Don W Cleveland (2013 Feb 7) A two-step mechanism for epigenetic specification of centromere identity and function. Nature cell biology : 1056-66 : DOI : 10.1038/ncb2805 Résumé The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENPA substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATDcontaining chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively. Année de publication : 2012 Andrew J Holland, Daniele Fachinetti, Quan Zhu, Manuel Bauer, Inder M Verma, Erich A Nigg, Don W Cleveland (2012 Dec 20) The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes & development : 2684-9 : DOI : 10.1101/gad.207027.112 Résumé Centrioles organize the centrosome, and accurate control of their number is critical for the maintenance of genomic integrity. Centriole duplication occurs once per cell cycle and is controlled by Polo-like kinase 4 (Plk4). We showed previously that Plk4 phosphorylates itself to promote its degradation by the proteasome. Here we demonstrate that this autoregulated instability controls the abundance of endogenous Plk4. Preventing Plk4 autoregulation causes centrosome amplification, stabilization of p53, and loss of cell proliferation; moreover, suppression of p53 allows growth of cells carrying amplified centrosomes. Plk4 autoregulation thus guards against genome instability by limiting centrosome duplication to once per cell cycle. Andrew J Holland, Daniele Fachinetti, Joo Seok Han, Don W Cleveland (2012 Nov 12) INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Publications de l’équipe Mécanismes moléculaires de la dynamique des chromosomes Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America : E3350-7 : DOI : 10.1073/pnas.1216880109 Résumé Inducible degradation is a powerful approach for identifying the function of a specific protein or protein complex. Recently, a plant auxin-inducible degron (AID) system has been shown to degrade AID-tagged target proteins in nonplant cells. Here, we demonstrate that an AIDtagged protein can functionally replace an endogenous protein depleted by RNAi, leading to an inducible null phenotype rapidly after auxin addition. The AID system is shown to be capable of controlling the stability of AID-tagged proteins that are in either nuclear or cytoplasmic compartments and even when incorporated into protein complexes. Induced degradation occurs rapidly after addition of auxin with protein half-life reduced to as little as 9 min and proceeding to completion with first-order kinetics. AID-mediated instability is demonstrated to be rapidly reversible. Induced degradation is shown to initiate and continue in all cell cycle phases, including mitosis, making this system especially useful for identifying the function(s) of proteins of interest during specific points in the mammalian cell cycle. Andrew J Holland, Daniele Fachinetti, Sandrine Da Cruz, Quan Zhu, Benjamin Vitre, Mariana Lince-Faria, Denaly Chen, Nicole Parish, Inder M Verma, Monica Bettencourt-Dias, Don W Cleveland (2012 Mar 30) Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis. Molecular biology of the cell : 1838-45 : DOI : 10.1091/mbc.E11-12-1043 Résumé Centrioles organize the centrosome, and accurate control of their number is critical for the maintenance of genomic integrity. Centrioles duplicate once per cell cycle, and duplication is coordinated by Polo-like kinase 4 (Plk4). We previously demonstrated that Plk4 accumulation is autoregulated by its own kinase activity. However, loss of heterozygosity of Plk4 in mouse embryonic fibroblasts has been proposed to cause cytokinesis failure as a primary event, leading to centrosome amplification and gross chromosomal abnormalities. Using targeted gene disruption, we show that human epithelial cells with one inactivated Plk4 allele undergo neither cytokinesis failure nor increase in centrosome amplification. Plk4 is shown to localize exclusively at the centrosome, with none in the spindle midbody. Substantial depletion of Plk4 by small interfering RNA leads to loss of centrioles and subsequent spindle defects that lead to a modest increase in the rate of cytokinesis failure. Therefore, Plk4 is a centriolelocalized kinase that does not directly regulate cytokinesis. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2