title: Chemical Genetic Screen Identifies Natural Products that Modulate Centriole Number.
abstract: Centrioles are microtubule-based organelles found in most eukaryotic cells and that are critical for the formation of cilia and flagella, as well as of centrosomes in animal cells. The number of centrioles must be strictly regulated in proliferating cells in order to ensure genome integrity upon cell division. Despite their importance, however, the mechanisms governing centriole assembly and number control remain incompletely understood, owing in part to a paucity of available small-molecule compounds for dissection and alteration of the underlying processes. Here we have developed a chemical genetic approach to identify small-molecule compounds capable of modulating centriole numbers in human cells. High-throughput screening of ≈2600 natural compounds identified 14 candidate molecules that either diminish (ten compounds) or augment (four compounds) the number of centrioles per cell. We investigated the mechanisms of action of four of these compounds and discovered that two of them potentially reduce centriole number through effects on NF-κB signalling. Moreover, we established that one further compound blocks cell cycle progression and probably indirectly causes an augmentation of centriole number. The last compound analysed induces, in addition to excess centrioles, exceptionally long primary cilia-like structures. Overall, our analysis demonstrates that natural products constitute a rich source of tool compounds useful for unravelling and manipulating the mechanisms governing centriole assembly and number control.
authors: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland.|National Centre of Competence in Research (NCCR) in Chemical Biology, 1015, Lausanne, Switzerland.
authors: Michele
authors: M
authors: Graciotti
authors: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors: Zhou
authors: Z
authors: Fang
authors: Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland.|National Centre of Competence in Research (NCCR) in Chemical Biology, 1015, Lausanne, Switzerland.
authors: Kai
authors: K
authors: Johnsson
authors: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland. pierre.gonczy@epfl.ch.|National Centre of Competence in Research (NCCR) in Chemical Biology, 1015, Lausanne, Switzerland. pierre.gonczy@epfl.ch.
authors: Pierre
authors: 0000-0002-6305-6883
authors: P
authors: Gönczy
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002502:Centrioles / Q000187:drug effects*; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D001688:Biological Products; D054852:Small Molecule Libraries
keywords: cell cycle; centriole; chemical genetics; high-throughput screening; natural products