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Open access
Journal of Biological Chemistry, volume 292, issue 11, pages 4593-4601

Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes

Hoffman Hunter G. 1
Rice Cory J. 2, 3
Skordalakes E. 1
1
 
From the Department of Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania 19104 and.
2
 
From the ‡Department of Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania 19104 and
3
 
the Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Publication typeJournal Article
Publication date2017-03-01
Quartile SCImago
Q1
Quartile WOS
Q2
Impact factor4.8
ISSN00219258, 1083351X
Biochemistry
Molecular Biology
Cell Biology
Abstract
Naturally occurring mutations in the ribonucleoprotein reverse transcriptase, telomerase, are associated with the bone marrow failure syndromes dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis. However, the mechanism by which these mutations impact telomerase function remains unknown. Here we present the structure of the human telomerase C-terminal extension (or thumb domain) determined by the method of single-wavelength anomalous diffraction to 2.31 Å resolution. We also used direct telomerase activity and nucleic acid binding assays to explain how naturally occurring mutations within this portion of telomerase contribute to human disease. The single mutations localize within three highly conserved regions of the telomerase thumb domain referred to as motifs E-I (thumb loop and helix), E-II, and E-III (the FVYL pocket, comprising the hydrophobic residues Phe-1012, Val-1025, Tyr-1089, and Leu-1092). Biochemical data show that the mutations associated with dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis disrupt the binding between the protein subunit reverse transcriptase of the telomerase and its nucleic acid substrates leading to loss of telomerase activity and processivity. Collectively our data show that although these mutations do not alter the overall stability or expression of telomerase reverse transcriptase, these rare genetic disorders are associated with an impaired telomerase holoenzyme that is unable to correctly assemble with its nucleic acid substrates, leading to incomplete telomere extension and telomere attrition, which are hallmarks of these diseases.

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Hoffman H. G. et al. Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes // Journal of Biological Chemistry. 2017. Vol. 292. No. 11. pp. 4593-4601.
GOST all authors (up to 50) Copy
Hoffman H. G., Rice C. J., Skordalakes E. Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes // Journal of Biological Chemistry. 2017. Vol. 292. No. 11. pp. 4593-4601.
RIS |
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RIS Copy
TY - JOUR
DO - 10.1074/jbc.M116.771204
UR - https://doi.org/10.1074%2Fjbc.M116.771204
TI - Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes
T2 - Journal of Biological Chemistry
AU - Hoffman, Hunter G.
AU - Rice, Cory J.
AU - Skordalakes, E.
PY - 2017
DA - 2017/03/01 00:00:00
PB - American Society for Biochemistry and Molecular Biology
SP - 4593-4601
IS - 11
VL - 292
PMID - 28154186
SN - 0021-9258
SN - 1083-351X
ER -
BibTex |
Cite this
BibTex Copy
@article{2017_Hoffman
author = {Hunter G. Hoffman and Cory J. Rice and E. Skordalakes},
title = {Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes},
journal = {Journal of Biological Chemistry},
year = {2017},
volume = {292},
publisher = {American Society for Biochemistry and Molecular Biology},
month = {mar},
url = {https://doi.org/10.1074%2Fjbc.M116.771204},
number = {11},
pages = {4593--4601},
doi = {10.1074/jbc.M116.771204}
}
MLA
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MLA Copy
Hoffman, Hunter G., et al. “Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes.” Journal of Biological Chemistry, vol. 292, no. 11, Mar. 2017, pp. 4593-4601. https://doi.org/10.1074%2Fjbc.M116.771204.
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