title: TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends.
abstract: Telomere synthesis in cancer cells and stem cells involves trafficking of telomerase to Cajal bodies, and telomerase is thought to be recruited to telomeres through interactions with telomere-binding proteins. Here, we show that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT. When tethered away from telomeres and other telomere-binding proteins, the TPP1 OB-fold domain is sufficient to recruit telomerase to a heterologous chromatin locus. Expression of a minimal TPP1 OB-fold inhibits telomere maintenance by blocking access of telomerase to its cognate binding site at telomeres. We identify amino acids required for the TPP1-telomerase interaction, including specific loop residues within the TPP1 OB-fold domain and individual residues within TERT, some of which are mutated in a subset of pulmonary fibrosis patients. These data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Franklin L
authors.initials: FL
authors.lastname: Zhong
authors.forename: Luis F Z
authors.initials: LF
authors.lastname: Batista
authors.forename: Adam
authors.initials: A
authors.lastname: Freund
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Pech
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Venteicher
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D020541:Coiled Bodies / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016415:Sequence Alignment; D000089804:Shelterin Complex; D019098:Telomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase