期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms14929
关键词
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资金
- Ministry of Science and Technology of China [2013CB910402]
- National Natural Science Foundation of China [31330040, 31525007, 31500625]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08010201]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- NCI [RO1 CA129037, R01 CA202816, R21 CA200506, R21 CA182280]
- CT Department of Public Health [15-002167]
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 TEBP alpha-beta 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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