title: Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome.
abstract: Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the beta-lactamase/beta-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Delta) in fibroblasts from a patient with HH syndrome. Apollo-Delta generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U768, 75015 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gaillard
authors.forename: Chantal
authors.initials: C
authors.lastname: Azerrad
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D002675:Child, Preschool; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005090:Exodeoxyribonucleases; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D020033:Protein Isoforms; D004247:DNA; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes