Progressive cis‐inhibition of telomerase upon telomere elongation

In yeast, the constant length of telomeric DNA results from a negative regulation of telomerase by the telomere itself. Here we follow the return to equilibrium of an abnormally shortened telomere. We observe that telomere elongation is restricted to a few base pairs per generation and that its rate decreases progressively with increasing telomere length. In contrast, in the absence of telomerase or in the presence of an over‐elongated telomere, the degradation rate linked to the succession of generations appears to be constant, i.e. independent of telomere length. Together, these results indicate that telomerase is gradually inhibited at its site of action by the elongating telomere. The implications of this finding for the dynamics of telomere length regulation are discussed in this study.

[1]  L. Sabatier,et al.  Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process , 1999, Oncogene.

[2]  J. Murnane,et al.  Chromosome healing in mouse embryonic stem cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Runge,et al.  The Yeast Telomere Length Counting Machinery Is Sensitive to Sequences at the Telomere-Nontelomere Junction , 1999, Molecular and Cellular Biology.

[4]  T. Cech,et al.  Two modes of survival of fission yeast without telomerase. , 1998, Science.

[5]  E. Blackburn,et al.  Rap1 protein regulates telomere turnover in yeast. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Jian Li,et al.  The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities , 1998, Current Biology.

[7]  S. Dupuis,et al.  Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase , 1998, Nature Genetics.

[8]  James E. Haber,et al.  Telomere maintenance is dependent on activities required for end repair of double-strand breaks , 1998, Current Biology.

[9]  T. Cech,et al.  Modulation of telomerase activity by telomere DNA-binding proteins in Oxytricha. , 1998, Genes & development.

[10]  R. Wellinger,et al.  Yeast Ku as a regulator of chromosomal DNA end structure. , 1998, Science.

[11]  V. Lundblad,et al.  The telomerase reverse transcriptase: components and regulation. , 1998, Genes & development.

[12]  T. Cech,et al.  Reversing Time: Origin of Telomerase , 1998, Cell.

[13]  Bas van Steensel,et al.  TRF2 Protects Human Telomeres from End-to-End Fusions , 1998, Cell.

[14]  C. Price Synthesis of the telomeric C-strand. A review. , 1997, Biochemistry. Biokhimiia.

[15]  D. Broccoli,et al.  Human telomeres contain two distinct Myb–related proteins, TRF1 and TRF2 , 1997, Nature Genetics.

[16]  E. Gilson,et al.  Telomeric localization of TRF2, a novel human telobox protein , 1997, Nature Genetics.

[17]  E. Gilson,et al.  Proteins that bind to double-stranded regions of telomeric DNA. , 1997, Trends in cell biology.

[18]  T R Hughes,et al.  Reverse transcriptase motifs in the catalytic subunit of telomerase. , 1997, Science.

[19]  D. Shore,et al.  A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. , 1997, Genes & development.

[20]  J. Langmore,et al.  Long G Tails at Both Ends of Human Chromosomes Suggest a C Strand Degradation Mechanism for Telomere Shortening , 1997, Cell.

[21]  E. Nimmo,et al.  Regulation of telomere length and function by a Myb-domain protein in fission yeast , 1997, Nature.

[22]  Bas van Steensel,et al.  Control of telomere length by the human telomeric protein TRF1 , 1997, Nature.

[23]  E. Blackburn,et al.  Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro. , 1997, Genes & development.

[24]  D. Shore,et al.  A Protein-Counting Mechanism for Telomere Length Regulation in Yeast , 1997, Science.

[25]  B. van Steensel,et al.  Control of telomere length by the human telomeric protein TRF1 , 1997, Nature.

[26]  D. Morris,et al.  Est1 has the properties of a single-stranded telomere end-binding protein. , 1996, Genes & development.

[27]  T. Lendvay,et al.  Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. , 1996, Genetics.

[28]  S. Jackson,et al.  Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. , 1996, Nucleic acids research.

[29]  T R Hughes,et al.  Cdc13p: A Single-Strand Telomeric DNA-Binding Protein with a Dual Role in Yeast Telomere Maintenance , 1996, Science.

[30]  E. Gilson,et al.  Chromatin: A sticky silence , 1996, Current Biology.

[31]  E. Blackburn,et al.  Control of telomere growth by interactions of RAP1 with the most distal telomeric repeats , 1996, Nature.

[32]  E. Blackburn,et al.  Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase. , 1996, Genes & development.

[33]  A. Lustig,et al.  A novel mechanism for telomere size control in Saccharomyces cerevisiae. , 1996, Genes & development.

[34]  D. Shore,et al.  Silencing of genes at nontelomeric sites in yeast is controlled by sequestration of silencing factors at telomeres by Rap 1 protein. , 1996, Genes & development.

[35]  H. Tanke,et al.  Heterogeneity in telomere length of human chromosomes. , 1996, Human molecular genetics.

[36]  J. Broach,et al.  Silencers are required for inheritance of the repressed state in yeast. , 1996, Genes & development.

[37]  E. Gilson,et al.  The telobox, a Myb-related telomeric DNA binding motif found in proteins from yeast, plants and human. , 1996, Nucleic acids research.

[38]  T. Petes,et al.  The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae. , 1996, Nucleic acids research.

[39]  C. Greider,et al.  Telomere length regulation. , 1996, Annual review of biochemistry.

[40]  V A Zakian,et al.  Telomeres: Beginning to Understand the End , 1995, Science.

[41]  H. Erdjument-Bromage,et al.  A Human Telomeric Protein , 1995, Science.

[42]  T. Cech,et al.  Telomerase and DNA end replication: no longer a lagging strand problem? , 1995, Science.

[43]  E. Blackburn,et al.  Runaway telomere elongation caused by telomerase RNA gene mutations , 1995, Nature.

[44]  B. Kennedy,et al.  Mutation in the silencing gene S/R4 can delay aging in S. cerevisiae , 1995, Cell.

[45]  D. Gottschling,et al.  Transcription of a yeast telomere alleviates telomere position effect without affecting chromosome stability. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Lustig,et al.  Mutational analysis defines a C-terminal tail domain of RAP1 essential for Telomeric silencing in Saccharomyces cerevisiae. , 1994, Genetics.

[47]  D. Gottschling,et al.  TLC1: template RNA component of Saccharomyces cerevisiae telomerase. , 1994, Science.

[48]  T. de Lange,et al.  Unusual chromatin in human telomeres , 1994, Molecular and cellular biology.

[49]  Virginia A. Zakian,et al.  Loss of a yeast telomere: Arrest, recovery, and chromosome loss , 1993, Cell.

[50]  E. Gilson,et al.  Distortion of the DNA double helix by RAP1 at silencers and multiple telomeric binding sites. , 1993, Journal of molecular biology.

[51]  E. Gilson,et al.  Telomeres and the functional architecture of the nucleus. , 1993, Trends in cell biology.

[52]  Michael A. Barnett,et al.  Telomere directed fragmentation of mammalian chromosomes , 1993, Nucleic Acids Res..

[53]  E. Gilson,et al.  The positioning of yeast telomeres depends on SIR3, SIR4, and the integrity of the nuclear membrane. , 1993, Cold Spring Harbor symposia on quantitative biology.

[54]  A. Lustig,et al.  C-terminal truncation of RAP1 results in the deregulation of telomere size, stability, and function in Saccharomyces cerevisiae , 1992, Molecular and cellular biology.

[55]  A. Lustig Hoogsteen G-G base pairing is dispensable for telomere healing in yeast. , 1992, Nucleic acids research.

[56]  F. Klein,et al.  Localization of RAP1 and topoisomerase II in nuclei and meiotic chromosomes of yeast , 1992, The Journal of cell biology.

[57]  J. Wright,et al.  Saccharomyces telomeres assume a non-nucleosomal chromatin structure. , 1992, Genes & development.

[58]  Oscar M. Aparicio,et al.  Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae , 1991, Cell.

[59]  A. Wolf,et al.  RAP1 protein interacts with yeast telomeres in vivo: Overproduction alters telomere structure and decreases chromosome stability , 1990, Cell.

[60]  Barbara L. Billington,et al.  Position effect at S. cerevisiae telomeres: Reversible repression of Pol II transcription , 1990, Cell.

[61]  D. Shore,et al.  Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length , 1990, Science.

[62]  J. Szostak,et al.  A mutant with a defect in telomere elongation leads to senescence in yeast , 1989, Cell.

[63]  A. Murray,et al.  Characterization of two telomeric DNA processing reactions in Saccharomyces cerevisiae , 1988, Molecular and Cellular Biology.

[64]  J. Rine,et al.  Replication and segregation of plasmids containing cis-acting regulatory sites of silent mating-type genes in Saccharomyces cerevisiae are controlled by the SIR genes , 1987, Molecular and cellular biology.

[65]  A. Murray,et al.  Roles of the 2 microns gene products in stable maintenance of the 2 microns plasmid of Saccharomyces cerevisiae , 1987, Molecular and cellular biology.

[66]  Drena D. Larson,et al.  Dynamics of telomere length variation in tetrahymena thermophila , 1987, Cell.

[67]  J. Broach,et al.  Site-specific recombination promotes plasmid amplification in yeast , 1986, Cell.

[68]  R. Walmsley,et al.  Genetic control of chromosome length in yeast. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Szostak,et al.  Transfer of yeast telomeres to linear plasmids by recombination , 1984, Cell.

[70]  Jack W. Szostak,et al.  DNA sequences of telomeres maintained in yeast , 1984, Nature.

[71]  J. D. Watson Origin of Concatemeric T7DNA , 1972 .

[72]  J. Yudkin Sugar and Disease , 1972, Nature.

[73]  B. Mcclintock,et al.  The Stability of Broken Ends of Chromosomes in Zea Mays. , 1941, Genetics.

[74]  A. Murray,et al.  Roles of the 2 , um Gene Products in Stable Maintenance of the 2 iim Plasmid of Saccharomyces cerevisiae , 2022 .