title: Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment.
abstract: Telomere maintenance is essential for organisms with linear chromosomes and is carried out by telomerase during cell cycle. The precise mechanism by which cell cycle controls telomeric access of telomerase and telomere elongation in mammals remains largely unknown. Previous work has established oligonucleotide/oligosaccharide binding (OB) fold-containing telomeric protein TPP1, formerly known as TINT1, PTOP, and PIP1, as a key factor that regulates telomerase recruitment and activity. However, the role of TPP1 in cell cycle-dependent telomerase recruitment is unclear. Here, we report that human TPP1 is phosphorylated at multiple sites during cell cycle progression and associates with higher telomerase activity at late S/G2/M. Phosphorylation of Ser111 (S111) within the TPP1 OB fold appears important for cell cycle-dependent telomerase recruitment. Structural analysis indicates that phosphorylated S111 resides in the telomerase-interacting domain within the TPP1 OB fold. Mutations that disrupt S111 phosphorylation led to decreased telomerase activity in the TPP1 complex and telomere shortening. Our findings provide insight into the regulatory pathways and structural basis that control cell cycle-dependent telomerase recruitment and telomere elongation through phosphorylation of TPP1.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-Sen University-Baylor College of Medicine Joint Research Center for Biomedical Sciences, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liuh-Yow
authors.initials: LY
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Hyeung
authors.initials: H
authors.lastname: Kim
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Zhou
authors.initials: Z
authors.lastname: Songyang
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D060888:Real-Time Polymerase Chain Reaction; D000089804:Shelterin Complex; D019098:Telomerase / Q000378:metabolism*; D034501:Telomere-Binding Proteins
chemical_list: C495876:ACD protein, human; D017931:DNA Primers; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase