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Nat Commun. 2017 Apr 10;8:14929. doi: 10.1038/ncomms14929.

Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.

Chen C1,2, Gu P3, Wu J1,2, Chen X1,2, Niu S1,2, Sun H1,2, Wu L1,2, Li N1,2, Peng J4, Shi S1,2, Fan C1,2, Huang M1,2, Wong CC1,2, Gong Q4, Kumar-Sinha C5, Zhang R1,2, Pusztai L6, Rai R3, Chang S3,7,8, Lei M1,2.

Author information

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.
Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut 05620, USA.
National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Department of 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.


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.

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