title: The Cul4-Ddb1(Cdt)² ubiquitin ligase inhibits invasion of a boundary-associated antisilencing factor into heterochromatin.
abstract: Partitioning of chromosomes into euchromatic and heterochromatic domains requires mechanisms that specify boundaries. The S. pombe JmjC family protein Epe1 prevents the ectopic spread of heterochromatin and is itself concentrated at boundaries. Paradoxically, Epe1 is recruited to heterochromatin by HP1 silencing factors that are distributed throughout heterochromatin. We demonstrate here that the selective enrichment of Epe1 at boundaries requires its regulation by the conserved Cul4-Ddb1(Cdt)² ubiquitin ligase, which directly recognizes Epe1 and promotes its polyubiquitylation and degradation. Strikingly, in cells lacking the ligase, Epe1 persists in the body of heterochromatin thereby inducing a defect in gene silencing. Epe1 is the sole target of the Cul4-Ddb1(Cdt)² complex whose destruction is necessary for the preservation of heterochromatin. This mechanism acts parallel with phosphorylation of HP1/Swi6 by CK2 to restrict Epe1. We conclude that the ubiquitin-dependent sculpting of the chromosomal distribution of an antisilencing factor is critical for heterochromatin boundaries to form correctly.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, 94158, USA.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Braun
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Garcia
authors.forename: Margot
authors.initials: M
authors.lastname: Rowley
authors.forename: Mathieu
authors.initials: M
authors.lastname: Rougemaille
authors.forename: Smita
authors.initials: S
authors.lastname: Shankar
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Madhani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C506543:Cdt2 protein, S pombe; D004268:DNA-Binding Proteins; C500125:Ddb1 protein, S pombe; D006570:Heterochromatin; D009687:Nuclear Proteins; D029702:Schizosaccharomyces pombe Proteins; C475031:epe1 protein, S pombe; D043743:Ubiquitin-Protein Ligase Complexes