Role of Oxidative Stress in Telomere Length Regulation and Replicative Senescence

Abstract: Replicative senescence is tied into organismal aging processes in more than one respect, and telomeres appear to be the major trigger of replicative senescence under many conditions in vitro and in vivo. However, the structure‐function relationships in telomeres, the mechanisms of telomere shortening with advancing replicative age, and the regulation of senescence by telomeres are far from understood. Combining recent data on telomere structure, function of telomere‐binding proteins, and sensitivity of telomeres to oxidative damage, an integrative model of telomere shortening and signaling is developed. The model suggests that t‐loop formation hinders access of repair proteins to telomeres, leading to accumulation of abasic sites and single‐strand breaks. These might contribute to accelerated telomere shortening by transient stalling of replication as well as, if present in high concentrations, to a relief of torsional tension which might destabilize the telomeric loop structure. As a result, the single‐stranded G‐rich overhang, which is present at the very ends of telomeres but is normally protected at the base of the telomeric loop, will be exposed to the nucleoplasm. Free G‐rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of the overhangs seems to be the first step in the signal transduction cascade to replicative senescence.

[1]  M. Muller,et al.  DNA topoisomerase II cleavage of telomeres in vitro and in vivo. , 1998, Biochimica et biophysica acta.

[2]  E. Blackburn,et al.  Telomerase: Dr Jekyll or Mr Hyde? , 1999, Current opinion in genetics & development.

[3]  R. Ward,et al.  Short telomeres on human chromosome 17p , 1998, Nature Genetics.

[4]  T. Zglinicki,et al.  Similar gene expression pattern in senescent and hyperoxic-treated fibroblasts. , 1998, The journals of gerontology. Series A, Biological sciences and medical sciences.

[5]  J. Remacle,et al.  Reciprocal Relationships between the Resistance to Stresses and Cellular Aging a , 1998, Annals of the New York Academy of Sciences.

[6]  K. Dittmann,et al.  Selective enrichment and biochemical characterization of seven human skin fibroblasts cell types in vitro. , 1989, Experimental cell research.

[7]  S. Oikawa,et al.  Site‐specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening , 1999, FEBS letters.

[8]  J. Wang,et al.  Effects of yeast DNA topoisomerase III on telomere structure. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Petersen,et al.  Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. , 1998, Experimental cell research.

[10]  T. Zglinicki,et al.  Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. , 2000, Free radical biology & medicine.

[11]  A. Olovnikov.  [Principle of marginotomy in template synthesis of polynucleotides]. , 1971, Doklady Akademii nauk SSSR.

[12]  J. Griffith,et al.  Mammalian Telomeres End in a Large Duplex Loop , 1999, Cell.

[13]  et al.,et al.  The RNA component of human telomerase , 1995, Science.

[14]  M. Duguet,et al.  When helicase and topoisomerase meet! , 1997, Journal of cell science.

[15]  S. Linn,et al.  Sequence-specific DNA Cleavage by Fe2+-mediated Fenton Reactions Has Possible Biological Implications* , 1999, The Journal of Biological Chemistry.

[16]  G. Saretzki,et al.  Accelerated telomere shortening in fibroblasts after extended periods of confluency. , 1998, Free radical biology & medicine.

[17]  J. Griffith,et al.  TRF1 promotes parallel pairing of telomeric tracts in vitro. , 1998, Journal of molecular biology.

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

[19]  T. Shibata,et al.  Homologous pairing and topological linkage of DNA molecules by combined action of E. coli recA protein and topoisomerase I , 1981, Cell.

[20]  D. Broccoli,et al.  p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. , 1999, Science.

[21]  T. Zglinicki,et al.  Lipofuscin accumulation and ageing of fibroblasts. , 1995, Gerontology.

[22]  J. Griffith,et al.  Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand. , 1999, Journal of molecular biology.

[23]  B. Ames,et al.  Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B. Bridges.  DNA repair: Polymerases for passing lesions , 1999, Current Biology.

[25]  R. Allsopp.  Models of initiation of replicative senescence by loss of telomeric DNA , 1996, Experimental Gerontology.

[26]  V. Dulic,et al.  Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts , 1999, Molecular and Cellular Biology.

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

[28]  C. Harley,et al.  Extension of life-span by introduction of telomerase into normal human cells. , 1998, Science.

[29]  G. Saretzki,et al.  Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? , 1995, Experimental cell research.

[30]  R. Wurm,et al.  Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments , 1999, Oncogene.

[31]  J. Shay,et al.  Normal human chromosomes have long G-rich telomeric overhangs at one end. , 1997, Genes & development.

[32]  M. Serrano,et al.  p19ARF links the tumour suppressor p53 to Ras , 1998, Nature.

[33]  S. Lejnine,et al.  Nucleosomal organization of telomere-specific chromatin in rat , 1993, Cell.

[34]  M. Meyn,et al.  Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Lynda Chin,et al.  E.: “A Summary of , 1968 .

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

[37]  T. Shibata,et al.  D-loop cycle. A circular reaction sequence which comprises formation and dissociation of D-loops and inactivation and reactivation of superhelical closed circular DNA promoted by recA protein of Escherichia coli. , 1982, The Journal of biological chemistry.

[38]  T. Suzuki,et al.  DNA topoisomerase inhibitors induce reversible senescence in normal human fibroblasts. , 1998, Biochemical and biophysical research communications.

[39]  Robert E. Johnson,et al.  hRAD30 mutations in the variant form of xeroderma pigmentosum. , 1999, Science.

[40]  J. Register,et al.  Direct visualization of RecA protein binding to and unwinding duplex DNA following the D-loop cycle. , 1988, The Journal of biological chemistry.

[41]  P. Baumann,et al.  Human Rad51 Protein Promotes ATP-Dependent Homologous Pairing and Strand Transfer Reactions In Vitro , 1996, Cell.

[42]  C. Harley,et al.  Evidence for a critical telomere length in senescent human fibroblasts. , 1995, Experimental cell research.

[43]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[44]  T. Davison,et al.  ATM‐dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post‐translational activation of p53 protein involving poly(ADP‐ribose) polymerase , 1997, The EMBO journal.

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

[46]  P. Hanawalt,et al.  T4-endonuclease V-sensitive sites in DNA from ultraviolet-irradiated human cells. , 1976, Biochimica et biophysica acta.

[47]  C. Schewe,et al.  Mitochondrial water loss and aging of cells , 1995, Cell biochemistry and function.