Review
DNA Ends: Just the Beginning (Nobel Lecture)†
Prof. Jack W. Szostak,
Prof. Jack W. Szostak
Department of Genetics, Harvard Medical School, 185 Cambridge Street, CCIB 7215 Simches Research Center, Boston, MA 02114 (USA)
Search for more papers by this authorProf. Jack W. Szostak,
Prof. Jack W. Szostak
Department of Genetics, Harvard Medical School, 185 Cambridge Street, CCIB 7215 Simches Research Center, Boston, MA 02114 (USA)
Search for more papers by this author†
Copyright© The Nobel Foundation 2009. We thank the Nobel Foundation, Stockholm, for permission to print this lecture.
Graphical Abstract
Secrets revealed: The Nobel Prize for Medicine 2009 was awarded for the solution to one of the greatest mysteries of biology: how are chromosomes copied upon cell division and protected from degradation? The answer can be found at the ends of the chromosomes—the telomeres—and in the enzyme that forms them—telomerase. The laureates describe the events leading to the discovery first-hand.
References
- 1“Sexual induction in Eudorina: effects of light, nutrients and conditioned medium”: J. W. Szostak, J. Sparkuhl, M. E. Goldstein, J. Phycol. 1973, 9, 215–218.
- 2“Specific binding of a synthetic oligonucleotide to yeast cytochrome c mRNA”: J. W. Szostak, J. I. Stiles, C. P. Bahl, R. Wu, Nature 1977, 265, 61–63.
- 3“Ray Wu, as remembered by a former student”: J. W. Szostak, Sci. China C Life Sci. 2009, 52, 108–110.
- 4“Transformation of yeast”: A. Hinnen, J. B. Hicks, G. R. Fink, Proc. Natl. Acad. Sci. USA 1978, 75, 1929–1933.
- 5“Unequal crossing over in the ribosomal DNA of Saccharomyces cerevisiae”: J. W. Szostak, R. Wu, Nature 1980, 284, 426–430.
- 6“Yeast transformation: a model system for the study of recombination”: T. L. Orr-Weaver, J. W. Szostak, R. J. Rothstein, Proc. Natl. Acad. Sci. USA 1981, 78, 6354–6358.
- 7 “The double-strand-break repair model for recombination”: J. W. Szostak, T. L. Orr-Weaver, R. J. Rothstein, F. Stahl, Cell 1983, 33, 25–35.
- 8“A mutant with a defect in telomere elongation leads to senescence in yeast”: V. Lundblad, J. W. Szostak, Cell 1989, 57, 633–643.
- 9“In vitro selection of RNA molecules that bind specific ligands”: A. E. Ellington, J. W. Szostak, Nature 1990, 346, 818–822.
- 10“Isolation of new ribozymes from a large pool of random sequences”: D. P. Bartel, J. W. Szostak, Science 1993, 261, 1411–1418.
- 11“RNA-peptide fusions for the in vitro selection of peptides and proteins”: R. W. Roberts, J. W. Szostak, Proc. Natl. Acad. Sci. USA 1997, 94, 12297–12302.
- 12“Functional proteins from a random sequence library”: A. D. Keefe, J. W. Szostak, Nature 2001, 410, 715–718.
- 13“Synthesizing life”: J. W. Szostak, D. P. Bartel, P. L. Luisi, Nature 2001, 409, 387–390.
- 14“Efficient and rapid template-directed nucleic acid copying using 2′-amino-2′, 3′-dideoxyribonucleoside-5′-phosphorimidazolide monomers”: J. Schrum, A. Ricardo, K. Krishnamurthy, J. C. Blain, J. W. Szostak, J. Am. Chem. Soc. 2009, 31, 14560–14570.
- 15“Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions”: M. W. Powner, B. Gerland, J. D. Sutherland, Nature 2009, 459, 239.
- 16“The remaking of chromosomes”: H. J. Muller, Collecting Net 1938, 13, 181–198.
- 17“Cytological observations of deficiencies involving known genes, translocations and an inversion in Zea mays”: B. McClintock, Mo. Agr. Exp. Sta. Res. Bull. 1931, 163, 4.
- 18“Origin of concatameric T7 DNA”: J. D. Watson, Nature New Biol. 1972, 239, 197–201.
- 19“A theory of marginotomy”: A. M. Olovnikov, J. Theor. Biol. 1973, 41, 181–190.
- 20“Transformation of yeast”: A. Hinnen, J. B. Hicks, G. R. Fink, Proc. Natl. Acad. Sci. USA 1978, 75, 1929–1933.
- 21“Yeast transformation: A model system for the study of recombination”: T. L. Orr-Weaver, J. W. Szostak, R. J. Rothstein, Proc. Natl. Acad. Sci. USA 1981, 78, 6354–6358.
- 22“Yeast recombination: The association between double-strand-gap repair and crossing-over”: T. L. Orr-Weaver, J. W. Szostak, Proc. Natl. Acad. Sci. USA 1983, 80, 4417–4421.
- 23“High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules”: K. Struhl, D. T. Stinchcomb, S. Scherer, R. W. Davis, Proc. Natl. Acad. Sci. USA 1979, 76, 1035–1039.
- 24“Isolation and characterisation of a yeast chromosomal replicator”: D. T. Stinchcomb, K. Struhl, R. W. Davis, Nature 1979, 282, 39–43.
- 25“The double-strand-break repair model for recombination”: J. W. Szostak, T. L. Orr-Weaver, R. J. Rothstein, F. Stahl, Cell 1983, 33, 25–35.
- 26“A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena”: E. H. Blackburn, J. G. Gall, J. Mol. Biol. 1978, 120, 33–53.
- 27“Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena”: K. Kruger, P. J. Grabowski, A. J. Zaug, J. Sands, D. E. Gottschling, T. R. Cech, Cell 1982, 31, 147–157.
- 28“Functional expression of cloned yeast DNA in Escherichia coli”: B. Ratzkin, J. Carbon, Proc. Natl. Acad. Sci. USA 1977, 74, 487–491.
- 29“Production of a functional eukaryotic enzyme in Escherichia coli: cloning and expression of the yeast structural gene for imidazole-glycerolphosphate dehydratase (his3)”: K. Struhl, R. W. Davis, Proc. Natl. Acad. Sci. USA 1977, 74, 5255–5259.
- 30“Cloning yeast telomeres on linear plasmid vectors”: J. W. Szostak, E. H. Blackburn, Cell 1982, 29, 245–255.
- 31“Is there left-handed DNA at the ends of yeast chromosomes?”: R. Walmsley, T. D. Petes, J. W. Szostak, Nature 1983, 302, 84–86.
- 32“DNA sequences of telomeres maintained in yeast”: J. Shampay, J. W. Szostak, E. H. Blackburn, Nature 1984, 310, 154–157.
- 33“Unusual DNA sequences associated with the ends of yeast chromosomes”: R. W. Walmsley, C. S. M. Chan, B.-K. Tye, T. D. Petes, Nature 1984, 310, 157–160.
- 34“Replication and Resolution of Telomeres in Yeast”: J. W. Szostak, Cold Spring Harbor Symp. Quant. Biol. 1983, 47, 1187–1194.
- 35“Isolation of a yeast centromere and construction of functional small circular chromosomes”: L. Clarke, J. Carbon, Nature 1980, 287, 504–509.
- 36“Construction of artificial chromosomes in yeast”: A. W. Murray, J. W. Szostak, Nature 1983, 305, 189–193.
- 37“Chromosome length controls mitotic chromosome segregation in yeast”: A. W. Murray, N. P. Schultes, J. W. Szostak, Cell 1986, 45, 529–536.
- 38“Arrest of segregation leads to accumulation of highly intertwined catenated dimers: dissection of the final stages of SV40 DNA replication”: O. Sundin, A. Varshavsky, Cell 1981, 25, 659–669.
- 39“Segregating sister genomes: the molecular biology of chromosome separation”: K. Nasmyth, Science 2002, 297, 559–565.
- 40“Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors”: D. T. Burke, G. F. Carle, M. V. Olson, Science 1987, 236, 806–812.
- 41“The molecular structure of centromeres and telomeres”: E. H. Blackburn, J. W. Szostak, Annu. Rev. Biochem. 1984, 53, 163–194.
- 42“Growth of chromosome ends in multiplying trypanosomes”: A. Bernards, P. A. Michels, C. R. Lincke, P. Borst, Nature 1983, 303, 592–597.
- 43“All gene-sized DNA molecules in four species of hypotrichs have the same terminal sequence and an unusual 3′ terminus”: L. A. Klobutcher, M. T. Swanton, P. Donini, D. M. Prescott, Proc. Natl. Acad. Sci. USA 1981, 78, 3015–3019.
- 44“Identification of a specific telomere terminal transferase activity in Tetrahymena extracts”: C. W. Greider, E. H. Blackburn, Cell 1985, 43, 405–413.
- 45“The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity”: C. W. Greider, E. H. Blackburn, Cell 1987, 51, 887–898.
- 46“How telomeres solve the end-protection problem”: T. de Lange, Science 2009, 326, 948–952.
- 47“A mutant with a defect in telomere elongation leads to senescence in yeast”: V. Lundblad, J. W. Szostak, Cell 1989, 57, 633–643.
- 48“In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs”: G. L. Yu, J. D. Bradley, L. D. Attardi, E. H. Blackburn, Nature 1990, 344, 126–132.
- 49“Telomeres shorten during ageing of human fibroblasts”: C. B. Harley, A. B. Futcher, C. W. Greider, Nature 1990, 345, 458–460.
- 50“Extension of life-span by introduction of telomerase into normal human cells”: A. G. Bodnar, M. Ouellette, M. Frolkis, S. E. Holt, C. P. Chiu, G. B. Morin, C. B. Harley, J. W. Shay, S. Lichtsteiner, W. E. Wright, Science 1998, 279, 349–352.
- 51“Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging”: E. H. Blackburn, C. W. Greider, J. W. Szostak, Nat. Med. 2006, 12, 1133–1138.
- 52“Telomerase activation. One step on the road to cancer?”: C. W. Greider, Trends Genet. 1999, 15, 109–112.
- 53“The RNA World”: W. Gilbert, Nature 1986, 319, 618.
- 54“RNA catalyzed synthesis of complementary strand RNA”: J. A. Doudna, J. W. Szostak, Nature 1989, 339, 519–522.
- 55“Selection of a ribozyme that functions as a superior template in a self-copying reaction”: R. Green, J. W. Szostak, Science 1992, 258, 1910–1915.
- 56“In vitro selection of RNA molecules that bind specific ligands”: A. E. Ellington, J. W. Szostak, Nature 1990, 346, 818–822.
- 57“Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase”: C. Tuerk, L. Gold, Science 1990, 249, 505–510.
- 58“An RNA motif that binds ATP”: M. Sassanfar, J. W. Szostak, Nature 1993, 364, 550–553.
- 59“Isolation of new ribozymes from a large pool of random sequences”: D. P. Bartel, J. W. Szostak, Science 1993, 261, 1411–1418.
- 60“Structurally complex and highly active RNA ligases derived from random RNA sequences”: E. H. Ekland, J. W. Szostak, D. P. Bartel, Science 1995, 269, 364–370.
- 61“Crystal structure of the catalytic core of an RNA-polymerase ribozyme”: D. M. Shechner, R. A. Grant, S. C. Bagby, Y. Koldobskaya, J. A. Piccirilli, D. P. Bartel, Science 2009, 326, 1271–1275.
- 62“RNA-catalysed RNA polymerization using nucleoside triphosphates”: E. H. Ekland, D. P. Bartel, Nature 1996, 383, 192–198.
- 63“A genome wide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene”: K. Salehi-Ashtiani, A. Luptak, S. Litovchick, J. W. Szostak, Science 2006, 313, 1788–1792.
- 64“Two previously undescribed members of the mouse CPEB family of genes and their inducible expression in the principal cell layers of the hippocampus”: M. Theis, K. Si, E. R. Kandel, Proc. Natl. Acad. Sci. USA 2003, 100, 9602–9607.
- 65“CPEB3 is associated with human episodic memory”: C. Vogler, K. Spalek, A. Aerni, P. Demougin, A. Müller, K.-D. Huynh, A. Papassotiropoulos, D. J.-F. de Quervain, Front. Behav. Neurosci. 2009, 3, 1–5.
- 66“RNA-peptide fusions for the in vitro selection of peptides and proteins”: R. W. Roberts, J. W. Szostak, Proc. Natl. Acad. Sci. USA 1997, 94, 12297–12302.
- 67“Functional proteins from a random sequence library”: A. D. Keefe, J. W. Szostak, Nature 2001, 410, 715–718.
- 68“Template-directed synthesis of a genetic polymer in a model protocell”: S. S. Mansy, J. P. Schrum, M. Krishnamurthy, S. Tobé, D. Treco, J. W. Szostak, Nature 2008, 454, 122–125.
- 69“Experimental models of primitive cellular compartments: Encapsulation, growth and division”: M. M. Hanczyc, S. M. Fujikawa, J. W. Szostak, Science 2003, 302, 618–622.
- 70“Synthesis of long prebiotic oligomers on mineral surfaces”: J. P. Ferris, A. R. Hill, Jr., R. Liu, L. E. Orgel, Nature 1996, 381, 59–61.
- 71“Coupled growth and division of model protocell membranes”: T. F. Zhu, J. W. Szostak, J. Am. Chem. Soc. 2009, 131, 5705–5713.
- 72“Molecular replication”: L. E. Orgel, Nature 1992, 358, 203–209.
- 73“Efficient and rapid template-directed nucleic acid copying using 2′-amino-2′,3′-dideoxyribonucleoside-5′-phosphorimidazolide monomers”: J. Schrum, A. Ricardo, K. Krishnamurthy, J. C. Blain, J. W. Szostak, J. Am. Chem. Soc. 2009, 131, 14560–14570.
