title: A Short CEP135 Splice Isoform Controls Centriole Duplication.
abstract: Centriole duplication is coordinated such that a single round of duplication occurs during each cell cycle. Disruption of this synchrony causes defects including supernumerary centrosomes in cancer and perturbed ciliary signaling [1-5]. To preserve the normal number of centrioles, the level, localization, and post-translational modification of centriole proteins is regulated so that, when centriole protein expression and/or activity are increased, centrioles self-assemble. Assembly is initiated by the formation of the cartwheel structure that comprises the base of centrioles [6-11]. SAS-6 constitutes the cartwheel, and SAS-6 levels remain low until centriole assembly is initiated at S phase onset [3, 12, 13]. CEP135 physically links to SAS-6 near the site of microtubule nucleation and binds to CPAP for triplet microtubule formation [13, 14]. We identify two distinct protein isoforms of CEP135 that antagonize each other to modulate centriole duplication: full-length CEP135 (CEP135(full)) promotes new assembly, whereas a short isoform, CEP135(mini), represses it. CEP135(mini) represses centriole duplication by limiting the centriolar localization of CEP135(full) binding proteins (SAS-6 and CPAP) and the pericentriolar localization of γ-tubulin. The CEP135 isoforms exhibit distinct and complementary centrosomal localization during the cell cycle. CEP135(mini) protein decreases from centrosomes upon anaphase onset. We suggest that the decrease in CEP135(mini) from centrosomes promotes centriole assembly. The repression of centriole duplication by a splice isoform of a protein that normally promotes it serves as a novel mechanism to limit centriole duplication.
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Dahl
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Divya Ganapathi
authors.initials: DG
authors.lastname: Sankaran
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bayless
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Pinter
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Domenico F
authors.initials: DF
authors.lastname: Galati
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA.
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Heasley
authors.affiliation: MCD Biology, University of Colorado at Boulder, 347 UCB, Boulder, CO 80309-0347, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Giddings
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine, 2801 East 17(th) Avenue, Aurora, CO 80045-2537, USA. Electronic address: chad.pearson@ucdenver.edu.
authors.forename: Chad G
authors.initials: CG
authors.lastname: Pearson
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002502:Centrioles / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D012326:RNA Splicing; D016196:S Phase; D014404:Tubulin / Q000378:metabolism
chemical_list: C534330:CEP135 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; C497202:SASS6 protein, human; D014404:Tubulin