Open Access
Proceedings of the National Academy of Sciences of the United States of America, volume 113, issue 46, pages 13021-13026
Structural and functional consequences of a disease mutation in the telomere protein TPP1
1
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109;
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2
Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109
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Publication type: Journal Article
Publication date: 2016-11-02
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11.1
ISSN: 00278424, 10916490
PubMed ID:
27807141
Multidisciplinary
Abstract
Significance Telomerase is an enzyme that replicates chromosome ends to facilitate continued stem cell division. Mutations in telomerase or in telomerase-related genes result in stem cell-dysfunction diseases, such as dyskeratosis congenita (DC). Despite its devastating nature, DC currently has no cure. Here we report the crystal structure of a mutant protein implicated in DC to reveal how the mutation disrupts a region of the protein essential for telomerase function. Furthermore, we demonstrated that this mutation, when introduced into a human cell line, is sufficient to cause the cellular underpinnings of DC. Our results therefore make the strong prediction that correcting the mutation in the stem cells of the patient will reverse the cellular symptoms of disease. Telomerase replicates chromosome ends to facilitate continued cell division. Mutations that compromise telomerase function result in stem cell failure diseases, such as dyskeratosis congenita (DC). One such mutation (K170Δ), residing in the telomerase-recruitment factor TPP1, provides an excellent opportunity to structurally, biochemically, and genetically dissect the mechanism of such diseases. We show through site-directed mutagenesis and X-ray crystallography that this TPP1 disease mutation deforms the conformation of two critical amino acids of the TEL [TPP1’s glutamate (E) and leucine-rich (L)] patch, the surface of TPP1 that binds telomerase. Using CRISPR-Cas9 technology, we demonstrate that introduction of this mutation in a heterozygous manner is sufficient to shorten telomeres in human cells. Our findings rule out dominant-negative effects of the mutation. Instead, these findings implicate reduced TEL patch dosage in causing telomere shortening. Our studies provide mechanistic insight into telomerase-deficiency diseases and encourage the development of gene therapies to counter such diseases.
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Bisht K. et al. Structural and functional consequences of a disease mutation in the telomere protein TPP1 // Proceedings of the National Academy of Sciences of the United States of America. 2016. Vol. 113. No. 46. pp. 13021-13026.
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Bisht K., Smith E. M., Tesmer V. M., Nandakumar J. Structural and functional consequences of a disease mutation in the telomere protein TPP1 // Proceedings of the National Academy of Sciences of the United States of America. 2016. Vol. 113. No. 46. pp. 13021-13026.
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TY - JOUR
DO - 10.1073/pnas.1605685113
UR - https://doi.org/10.1073%2Fpnas.1605685113
TI - Structural and functional consequences of a disease mutation in the telomere protein TPP1
T2 - Proceedings of the National Academy of Sciences of the United States of America
AU - Bisht, Kamlesh
AU - Smith, Eric M.
AU - Tesmer, Valerie M.
AU - Nandakumar, Jayakrishnan
PY - 2016
DA - 2016/11/02 00:00:00
PB - Proceedings of the National Academy of Sciences (PNAS)
SP - 13021-13026
IS - 46
VL - 113
PMID - 27807141
SN - 0027-8424
SN - 1091-6490
ER -
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@article{2016_Bisht,
author = {Kamlesh Bisht and Eric M. Smith and Valerie M. Tesmer and Jayakrishnan Nandakumar},
title = {Structural and functional consequences of a disease mutation in the telomere protein TPP1},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2016},
volume = {113},
publisher = {Proceedings of the National Academy of Sciences (PNAS)},
month = {nov},
url = {https://doi.org/10.1073%2Fpnas.1605685113},
number = {46},
pages = {13021--13026},
doi = {10.1073/pnas.1605685113}
}
Cite this
MLA
Copy
Bisht, Kamlesh, et al. “Structural and functional consequences of a disease mutation in the telomere protein TPP1.” Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 46, Nov. 2016, pp. 13021-13026. https://doi.org/10.1073%2Fpnas.1605685113.