title: An HP1 isoform-specific feedback mechanism regulates Suv39h1 activity under stress conditions.
abstract: The presence of H3K9me3 and heterochromatin protein 1 (HP1) are hallmarks of heterochromatin conserved in eukaryotes. The spreading and maintenance of H3K9me3 is effected by the functional interplay between the H3K9me3-specific histone methyltransferase Suv39h1 and HP1. This interplay is complex in mammals because the three HP1 isoforms, HP1α, β, and γ, are thought to play a redundant role in Suv39h1-dependent deposition of H3K9me3 in pericentric heterochromatin (PCH). Here, we demonstrate that despite this redundancy, HP1α and, to a lesser extent, HP1γ have a closer functional link to Suv39h1, compared to HP1β. HP1α and γ preferentially interact in vivo with Suv39h1, regulate its dynamics in heterochromatin, and increase Suv39h1 protein stability through an inhibition of MDM2-dependent Suv39h1-K87 polyubiquitination. The reverse is also observed, where Suv39h1 increases HP1α stability compared HP1β and γ. The interplay between Suv39h1 and HP1 isoforms appears to be relevant under genotoxic stress. Specifically, loss of HP1α and γ isoforms inhibits the upregulation of Suv39h1 and H3K9me3 that is observed under stress conditions. Reciprocally, Suv39h1 deficiency abrogates stress-dependent upregulation of HP1α and γ, and enhances HP1β levels. Our work defines a specific role for HP1 isoforms in regulating Suv39h1 function under stress via a feedback mechanism that likely regulates heterochromatin formation.
authors.affiliation: a Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Raurell-Vila
authors.affiliation: a Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.|b Tissue Repair and Regeneration Group , Department of Systems Biology , Universitat de Vic, Universitat Central de Catalunya , Vic , Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Bosch-Presegue
authors.affiliation: a Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gonzalez
authors.affiliation: c Department of Genetics , Human Genetics Institute, Rutgers University , Piscataway , NJ , USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kane-Goldsmith
authors.affiliation: d Microcopy Unit, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Casal
authors.affiliation: e Fächerverbund Anatomie, Institut für Zell- und Neurobiologie, Charite - Universitätsmedizin , Berlin , Germany.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Brown
authors.affiliation: a Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Marazuela-Duque
authors.affiliation: e Fächerverbund Anatomie, Institut für Zell- und Neurobiologie, Charite - Universitätsmedizin , Berlin , Germany.|f Natural Sciences and Psychology, John Moores University , Liverpool , UK.
authors.forename: Prim B
authors.initials: PB
authors.lastname: Singh
authors.affiliation: c Department of Genetics , Human Genetics Institute, Rutgers University , Piscataway , NJ , USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Serrano
authors.affiliation: a Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) , L'Hospitalet de Llobregat, Barcelona , Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vaquero
mesh_terms: D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D025461:Feedback, Physiological; D006657:Histones / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C000715593:CBX1 protein, human; C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D020033:Protein Isoforms; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases
keywords: Genome organization; HP1α; HP1β; HP1γ; Suv39h1; genome stability; heterochromatin; stress response