Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants
Abstract
:1. Introduction
2. Materials and Methods
2.1. Nucleic Acid Sequences
2.2. Expression and Purification of tcTERT
2.3. tcTERT Single-Turnover Kinetics
2.4. Computer Simulations
3. Results
3.1. R194Q and K372N Disrupt the Electrostatic Environment of the dNTP’s Triphosphate
3.2. R340H and V342M Disrupt the DNA 3′-Terminus
3.3. A255V and Y256N Decrease TERT Sugar Fidelity through Distinct Mechanisms
tcTERT Variant | Incoming Nucleotide | kpol (s−1) | Kd (μM) | Catalytic Efficiency (μM−1 s−1) |
---|---|---|---|---|
R194Q | dGTP | 0.197 ± 0.004 | 161 ± 8 | 1.2 × 10−3 ± 6.7 × 10−5 |
A255V | dGTP | 0.31 ± 0.01 | 190 ± 23 | 1.6 × 10−3 ± 2.1 × 10−4 |
A255V | rGTP | 6.6 × 10−3 ± 3.9 × 10−4 | 1088 ± 149 | 6.1 × 10−6 ± 3.7 × 10−6 |
Y256N | dGTP | 6.7 ± 0.4 | 205 ± 32 | 3.3 × 10−2 ± 5.5 × 10−3 |
Y256N | rGTP | 0.60 ± 0.03 | 147 ± 18 | 4.1 × 10−3 ± 5.2 × 10−4 |
R340H | dGTP | 0.25 ± 0.01 | 1337 ± 129 | 1.9 × 10−4 ± 4.0 × 10−5 |
V342M | dGTP | 1.9 ± 0.1 | 126 ± 17 | 1.5 × 10−2 ± 2.1 × 10−3 |
K372N | dGTP | 10−2 ± 1.6 × 10−4 | 178 ± 8 | 6.2 × 10−5 ± 2.8 × 10−6 |
4. Discussion
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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hTERT Residue | tcTERT Residue | Disease Association | Reference |
---|---|---|---|
R631Q | R194Q | IPF | [43,44] |
A716V | A255V | AA, IPF, Cancer | [45,46,47] |
Y717N | Y256N | Cancer | [48] |
R865H | R340H | AA, IPF | [49] |
V867M | V342M | PF, DC | [43] |
K902N | K372N | DC | [13] |
D868 | D343 | ||
D869 | D344 | ||
Q833 | Q308 |
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Welfer, G.A.; Borin, V.A.; Cortez, L.M.; Opresko, P.L.; Agarwal, P.K.; Freudenthal, B.D. Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants. Genes 2023, 14, 281. https://doi.org/10.3390/genes14020281
Welfer GA, Borin VA, Cortez LM, Opresko PL, Agarwal PK, Freudenthal BD. Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants. Genes. 2023; 14(2):281. https://doi.org/10.3390/genes14020281
Chicago/Turabian StyleWelfer, Griffin A., Veniamin A. Borin, Luis M. Cortez, Patricia L. Opresko, Pratul K. Agarwal, and Bret D. Freudenthal. 2023. "Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants" Genes 14, no. 2: 281. https://doi.org/10.3390/genes14020281
APA StyleWelfer, G. A., Borin, V. A., Cortez, L. M., Opresko, P. L., Agarwal, P. K., & Freudenthal, B. D. (2023). Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants. Genes, 14(2), 281. https://doi.org/10.3390/genes14020281