title: Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication.
abstract: Eukaryotic up-frameshift 1 (UPF1) is a nucleic acid-dependent ATPase and 5'-to-3' helicase, best characterized for its roles in cytoplasmic RNA quality control. We previously demonstrated that human UPF1 binds to telomeres in vivo and its depletion leads to telomere instability. Here, we show that UPF1 is present at telomeres at least during S and G2/M phases and that UPF1 association with telomeres is stimulated by the phosphoinositide 3-kinase (PI3K)-related protein kinase ataxia telangiectasia mutated and Rad3-related (ATR) and by telomere elongation. UPF1 physically interacts with the telomeric factor TPP1 and with telomerase. Akin to UPF1 binding to telomeres, this latter interaction is mediated by ATR. Moreover, the ATPase activity of UPF1 is required to prevent the telomeric defects observed upon UPF1 depletion, and these defects stem predominantly from inefficient telomere leading-strand replication. Our results portray a scenario where UPF1 orchestrates crucial aspects of telomere biology, including telomere replication and telomere length homeostasis.
authors.affiliation: Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich, Switzerland.
authors.forename: Raghav
authors.initials: R
authors.lastname: Chawla
authors.forename: Sophie
authors.initials: S
authors.lastname: Redon
authors.forename: Christina
authors.initials: C
authors.lastname: Raftopoulou
authors.forename: Harry
authors.initials: H
authors.lastname: Wischnewski
authors.forename: Sarantis
authors.initials: S
authors.lastname: Gagos
authors.forename: Claus M
authors.initials: CM
authors.lastname: Azzalin
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D020543:Proteome; D040901:Proteomics; D020365:RNA Helicases; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure; D034501:Telomere-Binding Proteins; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C495876:ACD protein, human; D020543:Proteome; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D015534:Trans-Activators; D019098:Telomerase; D020365:RNA Helicases; C101828:UPF1 protein, human