title: A small GTPase molecular switch regulates epigenetic centromere maintenance by stabilizing newly incorporated CENP-A.
abstract: Epigenetic mechanisms regulate genome activation in diverse events, including normal development and cancerous transformation. Centromeres are epigenetically designated chromosomal regions that maintain genomic stability by directing chromosome segregation during cell division. The histone H3 variant CENP-A resides specifically at centromeres, is fundamental to centromere function and is thought to act as the epigenetic mark defining centromere loci. Mechanisms directing assembly of CENP-A nucleosomes have recently emerged, but how CENP-A is maintained after assembly is unknown. Here, we show that a small GTPase switch functions to maintain newly assembled CENP-A nucleosomes. Using functional proteomics, we found that MgcRacGAP (a Rho family GTPase activating protein) interacts with the CENP-A licensing factor HsKNL2. High-resolution live-cell imaging assays, designed in this study, demonstrated that MgcRacGAP, the Rho family guanine nucleotide exchange factor (GEF) Ect2, and the small GTPases Cdc42 and Rac, are required for stability of newly incorporated CENP-A at centromeres. Thus, a small GTPase switch ensures epigenetic centromere maintenance after loading of new CENP-A.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal P.O. Box 6128, Station Centre-Ville Montréal QC, H3C 3J7 Canada.
authors.forename: Anaïck
authors.initials: A
authors.lastname: Lagana
authors.forename: Jonas F
authors.initials: JF
authors.lastname: Dorn
authors.forename: Valérie
authors.initials: V
authors.lastname: De Rop
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ladouceur
authors.forename: Amy S
authors.initials: AS
authors.lastname: Maddox
authors.forename: Paul S
authors.initials: PS
authors.lastname: Maddox
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002503:Centromere / Q000378:metabolism*; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004261:DNA Replication; D044127:Epigenesis, Genetic; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D020559:Monomeric GTP-Binding Proteins