Structural and functional analysis of the human POT1-TPP1 telomeric complex

Nature Communications

Volumn 8, Issue , 2017, Pages

  Rice, Cory ^a,b   Shastrula, Prashanth Krishna ^a   Kossenkov, Andrew V ^a   Hills, Robert ^a   Baird, Duncan M ^c   Showe, Louise C ^a   Doukov, Tzanko ^d   Janicki, Susan ^a   Skordalakes, Emmanuel ^a,b  

^a WISTAR INSTITUTE   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c CARDIFF UNIVERSITY   (United Kingdom)

^d SLAC NATIONAL ACCELERATOR LABORATORY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HETERODIMER; MUTANT PROTEIN; NUCLEOPROTEIN; PROTEIN POT1; PROTEIN TPP1; RESOLVASE; TELOMERASE; UNCLASSIFIED DRUG; DNA; POT1 PROTEIN, HUMAN; PROTEIN BINDING; PTOP PROTEIN, HUMAN; TELOMERE BINDING PROTEIN;

BIOCHEMISTRY; CANCER; DNA; GENE EXPRESSION; GENETIC ANALYSIS; GENOMICS; MUTATION;

ARTICLE; CHROMOSOME ABERRATION; COMPLEX FORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DNA BINDING; GENOMIC INSTABILITY; MALIGNANT NEOPLASM; MUTATION; NONHUMAN; PROTEIN ASSEMBLY; PROTEIN DNA BINDING; PROTEIN DOMAIN; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; STRUCTURE ANALYSIS; TELOMERE; CALORIMETRY; CHEMISTRY; GENETICS; HEK293 CELL LINE; HUMAN; METABOLISM; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

CALORIMETRY; CRYSTALLOGRAPHY, X-RAY; DNA; HEK293 CELLS; HUMANS; MUTANT PROTEINS; MUTATION; PROTEIN BINDING; STRUCTURE-ACTIVITY RELATIONSHIP; TELOMERASE; TELOMERE; TELOMERE-BINDING PROTEINS;

EID: 85017354377     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms14928     Document Type: Article

References (45)

1. de Lange, T. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100-2110 (2005).
2. Liu, D., O'Connor, M. S., Qin, J., Songyang, Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J. Biol. Chem. 279, 51338-51342 (2004).
3. Liu, D., et al. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 6, 673-680 (2004).
4. Lei, M., Podell, E. R., Cech, T. R. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome endprotection. Nat. Struct. Mol. Biol. 11, 1223-1229 (2004).
5. Loayza, D., Parsons, H., Donigian, J., Hoke, K., de Lange, T. DNA binding features of human POT1: A nonamer 50-TAGGGTTAG-30 minimal binding site, sequence specificity, and internal binding to multimeric sites. J. Biol. Chem. 279, 13241-13248 (2004).
6. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S., de Lange, T. p53-A nd ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321-1325 (1999).
7. van Steensel, B., Smogorzewska, A., de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401-413 (1998).
8. Baumann, P., Cech, T. R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171-1175 (2001).
9. Wang, F., et al. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506-510 (2007).
10. Lei, M., Podell, E. R., Baumann, P., Cech, T. R. DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature 426, 198-203 (2003).
11. Nandakumar, J., Cech, T. R. DNA-induced dimerization of the singlestranded DNA binding telomeric protein Pot1 from Schizosaccharomyces pombe. Nucleic Acids Res. 40, 235-244 (2012).
12. He, Q., et al. G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression. Biochim. Biophys. Acta 1840, 2222-2233 2014.
13. Hockemeyer, D., Sfeir, A. J., Shay, J. W., Wright, W. E., de Lange, T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 24, 2667-2678 (2005).
14. Denchi, E. L., de Lange, T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068-1071 (2007).
15. Tong, A. S., et al. ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres. Cell Rep. 13, 1633-1646 (2015).
16. Xin, H., et al. TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445, 559-562 (2007).
17. Taylor, D. J., Podell, E. R., Taatjes, D. J., Cech, T. R. Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. J. Mol. Biol. 410, 10-17 (2011).
18. Abagyan, R., Totrov, M. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J. Mol. Biol. 235, 983-1002 (1994).
19. Zhang, Y., et al. Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc. Natl Acad. Sci. USA 110, 5457-5462 (2013).
20. Nandakumar, J., et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285-289 (2012).
21. Zaug, A. J., Podell, E. R., Cech, T. R. Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proc. Natl Acad. Sci. USA 102, 10864-10869 (2005).
22. Ramsay, A. J., et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat. Genet. 45, 526-530 (2013).
23. Robles-Espinoza, C. D., et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 46, 478-481 (2014).
24. Shi, J., et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 46, 482-486 (2014).
25. Bainbridge, M. N., et al. Germline mutations in shelterin complex genes are associated with familial glioma. J. Natl Cancer Inst. 107, 384 (2015).
26. Ferrandon, S., et al. Telomere profiling: Toward glioblastoma personalized medicine. Mol. Neurobiol. 47, 64-76 (2013).
27. Lin, T. T., et al. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: Evidence for a telomere crisis. Blood 116, 1899-1907 (2010).
28. Horvath, M. P., Schweiker, V. L., Bevilacqua, J. M., Ruggles, J. A., Schultz, S. C. Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA. Cell 95, 963-974 (1998).
29. Cristofari, G., Lingner, J. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J. 25, 565-574 (2006).
30. Loayza, D., De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013-1018 (2003).
31. Bailey, S. M., Murnane, J. P. Telomeres, chromosome instability and cancer. Nucleic Acids Res. 34, 2408-2417 (2006).
32. Sfeir, A., et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138, 90-103 (2009).
33. Webb, C. J., Wu, Y., Zakian, V. A. DNA repair at telomeres: Keeping the ends intact. Cold Spring Harb Perspect Biol 5, a012666 (2013).
34. Armbruster, B. N., et al. Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1. Mol. Cell Biol. 24, 3552-3561 (2004).
35. Colgin, L. M., Baran, K., Baumann, P., Cech, T. R., Reddel, R. R. Human POT1 facilitates telomere elongation by telomerase. Curr. Biol. 13, 942-946 (2003).
36. Veldman, T., Etheridge, K. T., Counter, C. M. Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr. Biol. 14, 2264-2270 (2004).
37. Ye, J. Z., et al. POT1-interacting protein PIP1: A telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649-1654 (2004).
38. Kelleher, C., Kurth, I., Lingner, J. Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol. Cell Biol. 25, 808-818 (2005).
39. Lei, M., Zaug, A. J., Podell, E. R., Cech, T. R. Switching human telomerase on and off with hPOT1 protein in vitro. J. Biol. Chem. 280, 20449-20456 (2005).
40. Speedy, H. E., et al. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 46, 56-60 (2014).
41. Lin, T. T., et al. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br. J. Haematol. 167, 214-223 (2014).
42. Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254 (1976).
43. Cristofari, G., et al. Low-to high-throughput analysis of telomerase modulators with Telospot. Nat. Methods 4, 851-853 (2007).
44. Latrick, C. M., Cech, T. R. POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J. 29, 924-933 (2010).
45. Gohring, J., Fulcher, N., Jacak, J., Riha, K. TeloTool: A new tool for telomere length measurement from terminal restriction fragment analysis with improved probe intensity correction. Nucleic Acids Res. 42, e21 (2014).