Open Access
Nature Communications, volume 8, issue 1, publication number 14929
Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
Chen Cong
1, 2
,
Gu Peili
3
,
Wu Jian
1, 2
,
Chen Xianyun
1, 2
,
Niu Shuangshuang
1, 2
,
Sun Hong
1, 2
,
Wu Lijie
1, 2
,
Li Na
1, 2
,
Peng Junhui
4
,
SHI SHAOHUA
1, 2
,
Fan Cuiying
1, 2
,
Huang Min
1, 2
,
Wong Catherine C. L.
1, 2
,
Gong Qingguo
4
,
Kumar-Sinha Chandan
5
,
Zhang Rongguang
1, 2
,
Pusztai Lajos
6
,
Rai Rekha
3
,
Chang Sandy
3, 7, 8
,
Lei Ming
1, 2
1
Shanghai Research Center, Chinese Academy of Sciences, Shanghai, China
|
2
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, Shanghai, China
|
3
Department of Laboratory Medicine, Yale School of Medicine, New Haven, USA
|
4
National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
|
5
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, USA
|
6
Department of Medicine, Yale School of Medicine, New Haven, USA
|
7
Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, USA
|
8
Department of Pathology, Yale School of Medicine, New Haven, USA
|
Publication type: Journal Article
Publication date: 2017-04-10
Journal:
Nature Communications
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 16.6
ISSN: 20411723
PubMed ID:
28393832
General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy
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. Human telomeres are protected by a specialized shelterin complex composed of six proteins. Here the authors structurally characterize the interaction between the POT1-TPP1 shelterin component and identify mutations associated with genome instability and cancer that disrupt the POT1-TPP1 interaction.
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Cite this
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RIS |
BibTex
Cite this
GOST
Copy
Chen C. et al. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer // Nature Communications. 2017. Vol. 8. No. 1. 14929
GOST all authors (up to 50)
Copy
Chen C., Gu P., Wu J., Chen X., Niu S., Sun H., Wu L., Li N., Peng J., SHI S., Fan C., Huang M., Wong C. C. L., Gong Q., Kumar-Sinha C., Zhang R., Pusztai L., Rai R., Chang S., Lei M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer // Nature Communications. 2017. Vol. 8. No. 1. 14929
Cite this
RIS
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TY - JOUR
DO - 10.1038/ncomms14929
UR - https://doi.org/10.1038%2Fncomms14929
TI - Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
T2 - Nature Communications
AU - Chen, Cong
AU - Gu, Peili
AU - Wu, Jian
AU - Chen, Xianyun
AU - Niu, Shuangshuang
AU - Sun, Hong
AU - Wu, Lijie
AU - Li, Na
AU - Peng, Junhui
AU - SHI, SHAOHUA
AU - Fan, Cuiying
AU - Huang, Min
AU - Wong, Catherine C. L.
AU - Gong, Qingguo
AU - Kumar-Sinha, Chandan
AU - Zhang, Rongguang
AU - Pusztai, Lajos
AU - Rai, Rekha
AU - Chang, Sandy
AU - Lei, Ming
PY - 2017
DA - 2017/04/10 00:00:00
PB - Springer Nature
IS - 1
VL - 8
PMID - 28393832
SN - 2041-1723
ER -
Cite this
BibTex
Copy
@article{2017_Chen,
author = {Cong Chen and Peili Gu and Jian Wu and Xianyun Chen and Shuangshuang Niu and Hong Sun and Lijie Wu and Na Li and Junhui Peng and SHAOHUA SHI and Cuiying Fan and Min Huang and Catherine C. L. Wong and Qingguo Gong and Chandan Kumar-Sinha and Rongguang Zhang and Lajos Pusztai and Rekha Rai and Sandy Chang and Ming Lei},
title = {Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer},
journal = {Nature Communications},
year = {2017},
volume = {8},
publisher = {Springer Nature},
month = {apr},
url = {https://doi.org/10.1038%2Fncomms14929},
number = {1},
doi = {10.1038/ncomms14929}
}