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Structural and functional consequences of a disease mutation in the telomere protein TPP1.

Bisht K, Smith EM, Tesmer VM, Nandakumar J
Proc Natl Acad Sci U S A 113 13021-13026 (2016)
Cited: 27 times
EuropePMC logo PMID: 27807141

Abstract

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.

Reviews - 5i2x mentioned but not cited (2)

  1. POT1-TPP1 telomere length regulation and disease. Aramburu T, Plucinsky S, Skordalakes E. Comput Struct Biotechnol J 18 1939-1946 (2020)
  2. Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations. Amir M, Khan P, Queen A, Dohare R, Alajmi MF, Hussain A, Islam A, Ahmad F, Hassan I. Cells 9 E359 (2020)

Articles - 5i2x mentioned but not cited (1)

  1. Structural and functional consequences of a disease mutation in the telomere protein TPP1. Bisht K, Smith EM, Tesmer VM, Nandakumar J. Proc Natl Acad Sci U S A 113 13021-13026 (2016)


Reviews citing this publication (7)

  1. Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Lim CJ, Cech TR. Nat Rev Mol Cell Biol 22 283-298 (2021)
  2. Structural biology of telomeres and telomerase. Smith EM, Pendlebury DF, Nandakumar J. Cell Mol Life Sci 77 61-79 (2020)
  3. Molecular mechanisms of telomere biology disorders. Grill S, Nandakumar J. J Biol Chem 296 100064 (2021)
  4. Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging. Gavia-García G, Rosado-Pérez J, Arista-Ugalde TL, Aguiñiga-Sánchez I, Santiago-Osorio E, Mendoza-Núñez VM. Biology (Basel) 10 253 (2021)
  5. Structural biology of telomerase and its interaction at telomeres. Wang Y, Feigon J. Curr Opin Struct Biol 47 77-87 (2017)
  6. Genetics of human telomere biology disorders. Revy P, Kannengiesser C, Bertuch AA. Nat Rev Genet 24 86-108 (2023)
  7. Molecular insight of dyskeratosis congenita: Defects in telomere length homeostasis. Dorgaleleh S, Naghipoor K, Hajimohammadi Z, Dastaviz F, Oladnabi M. J Clin Transl Res 8 20-30 (2022)

Articles citing this publication (17)

  1. The N Terminus of the OB Domain of Telomere Protein TPP1 Is Critical for Telomerase Action. Grill S, Tesmer VM, Nandakumar J. Cell Rep 22 1132-1140 (2018)
  2. CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length. Gu P, Jia S, Takasugi T, Smith E, Nandakumar J, Hendrickson E, Chang S. Aging Cell 17 e12783 (2018)
  3. Two Separation-of-Function Isoforms of Human TPP1 Dictate Telomerase Regulation in Somatic and Germ Cells. Grill S, Bisht K, Tesmer VM, Shami AN, Hammoud SS, Nandakumar J. Cell Rep 27 3511-3521.e7 (2019)
  4. Combining conservation and species-specific differences to determine how human telomerase binds telomeres. Tesmer VM, Smith EM, Danciu O, Padmanaban S, Nandakumar J. Proc Natl Acad Sci U S A 116 26505-26515 (2019)
  5. Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment. Liu Y, Liu F, Cao Y, Xu H, Wu Y, Wu S, Liu D, Zhao Y, Songyang Z, Ma W. Cell Rep 22 1849-1860 (2018)
  6. Letter Homozygous OB-fold variants in telomere protein TPP1 are associated with dyskeratosis congenita-like phenotypes. Tummala H, Collopy LC, Walne AJ, Ellison A, Cardoso S, Aksu T, Yarali N, Aslan D, Fikret Akata R, Teo J, Songyang Z, Pontikos N, Fitzgibbon J, Tomita K, Vulliamy T, Dokal I. Blood 132 1349-1353 (2018)
  7. A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family. Shao Y, Feng S, Huang J, Huo J, You Y, Zheng Y. BMC Med Genet 19 40 (2018)
  8. Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation. Yu Y, Jia W, Lyu Y, Su D, Bai M, Shen J, Qiao J, Han T, Liu W, Chen J, Chen W, Ye D, Guo X, Zhu S, Xi J, Zhu R, Wan X, Gao S, Zhu J, Kang J. Cell Discov 5 47 (2019)
  9. A lentivirus-free inducible CRISPR-Cas9 system for efficient targeting of human genes. Bisht K, Grill S, Graniel J, Nandakumar J. Anal Biochem 530 40-49 (2017)
  10. Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length. Henslee G, Williams CL, Liu P, Bertuch AA. Cold Spring Harb Mol Case Stud 7 a005454 (2021)
  11. Insights into the structure and function of Est3 from the Hansenula polymorpha telomerase. Shepelev NM, Mariasina SS, Mantsyzov AB, Malyavko AN, Efimov SV, Petrova OA, Rodina EV, Zvereva MI, Dontsova OA, Polshakov VI. Sci Rep 10 11109 (2020)
  12. TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis. Grill S, Padmanaban S, Friedman A, Perkey E, Allen F, Tesmer VM, Chase J, Khoriaty R, Keegan CE, Maillard I, Nandakumar J. JCI Insight 6 138059 (2021)
  13. The structurally conserved TELR region on shelterin protein TPP1 is essential for telomerase processivity but not recruitment. Sandhu R, Sharma M, Wei D, Xu L. Proc Natl Acad Sci U S A 118 e2024889118 (2021)
  14. Chemical shift assignments and the secondary structure of the Est3 telomerase subunit in the yeast Hansenula polymorpha. Mariasina SS, Efimov SV, Petrova OA, Rodina EV, Malyavko AN, Zvereva MI, Klochkov VV, Dontsova OA, Polshakov VI. Biomol NMR Assign 12 57-62 (2018)
  15. Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline. Graniel JV, Bisht K, Friedman A, White J, Perkey E, Vanderbeck A, Moroz A, Carrington LJ, Brandstadter JD, Allen F, Shami AN, Thomas P, Crayton A, Manzor M, Mychalowych A, Chase J, Hammoud SS, Keegan CE, Maillard I, Nandakumar J. Life Sci Alliance 5 e202101208 (2022)
  16. Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase. Aureli S, Cardenas VB, Raniolo S, Limongelli V. Commun Chem 6 242 (2023)
  17. Interaction hub critical for telomerase recruitment and primer-template handling for catalysis. Padmanaban S, Tesmer VM, Nandakumar J. Life Sci Alliance 6 e202201727 (2023)


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