title: Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.
abstract: Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα-β complex, POT1-TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C-TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut 05620, USA.
authors.forename: Peili
authors.initials: P
authors.lastname: Gu
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jian
authors.identifier: 0000-0002-2072-0967
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Chen
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Niu
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Wu
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Peng
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Shi
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Fan
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.affiliation: National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rongguang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, Connecticut 05620, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut 05620, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rai
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut 05620, USA.|Department of Pathology, Yale School of Medicine, New Haven, Connecticut 05620, USA.|Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, Connecticut 05620, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.|Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ming
authors.identifier: 0000-0002-1153-4791
authors.initials: M
authors.lastname: Lei
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D000089804:Shelterin Complex / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D034501:Telomere-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; D018832:Molecular Chaperones; C440849:POT1 protein, human; D010750:Phosphoproteins; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C490849:PTGES3 protein, human; D000071876:Prostaglandin-E Synthases