Long-term quiescent fibroblast cells transit into senescence

PLoS ONE

Volumn 9, Issue 12, 2014, Pages

  Marthandan, Shiva ^a   Priebe, Steffen ^b   Hemmerich, Peter ^a   Klement, Karolin ^c   Diekmann, Stephan ^a   Hofmann, Thomas G ^d  

^a FRITZ LIPMANN INSTITUTE   (Germany)

^b HANS KNÖLL INSTITUTE   (Germany)

^c UNIVERSITY OF CALGARY   (Canada)

^d GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

TRANSCRIPTION FACTOR HES 1; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; HES1 PROTEIN, HUMAN; HOMEODOMAIN PROTEIN;

APOPTOSIS; ARTICLE; CELL AGING; CELL KINETICS; CELL POPULATION; CELL PROLIFERATION; CELL SURVIVAL; CELLULAR PARAMETERS; CELLULAR QUIESCENCE; CONTROLLED STUDY; DNA DAMAGE; FIBROBLAST; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; OXIDATIVE STRESS; PROTEIN EXPRESSION; SENESCENCE; CELL CULTURE; CELL DIVISION; CYTOLOGY; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; PHYSIOLOGY; TELOMERE;

APOPTOSIS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CELL AGING; CELL DIVISION; CELL PROLIFERATION; CELLS, CULTURED; DNA DAMAGE; FIBROBLASTS; GENE EXPRESSION REGULATION; HOMEODOMAIN PROTEINS; HUMANS; TELOMERE;

EID: 84919798290     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0115597     Document Type: Article

References (135)

1. Pajalunga D, Mazzola A, Salzano AM, Biferi MG, De Luca G, et al. (2007) Critical requirement for cell cycle inhibitors in sustaining nonproliferative states. Journal of Cell Biology 176: 807-818.
2. Sherr CJ, Roberts JM (1999) CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes & Development 13(12): 1501-1512.
3. Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, et al. (2009) p53 Regulates Hematopoietic Stem Cell Quiescence. Cell Stem Cell 4(1): 37-48.
4. van Os R, de Haan G, Dykstra BJ (2009) Hematopoietic Stem Cell Quiescence: Yet another Role for p53. Cell Stem Cell 4(1): 7-8.
5. Asai T, Liu Y, Bae N, Nimer SD (2011) The p53 tumor suppressor protein regulates hematopoietic stem cell fate. Journal of Cellular Physiology 226(9): 2215-2221.
6. Dulic V (2011) Be quiet and you'll keep young: does mTOR underlie p53 action in protecting against senescence by favoring quiescence? Aging (Albany NY) 3(1): 3-4.
7. Bauer DE, Harris MH, Plas DR, Lum JJ, Hammerman PS, et al. (2004) Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. The FASEB Journal 18(11): 1303-1305.
8. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, et al. (2005) Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis. Cell 120(2): 237-248.
9. Lemons JMS, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, et al. (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biology 8(10): E1000514.
10. Grigoryev SA, Nikitina T, Pehrson JR, Singh PB, Woodcock CL (2004) Dynamic relocation of epigenetic chromatin markers reveals an active role of constitutive heterochromatin in the transition from proliferation to quiescence. Journal of Cell Science 117(25): 6153-6162.
11. Laporte D, Courtout F, Salin B, Ceschin J, Sagot I (2013) An array of nuclear microtubules reorganizes the budding yeast nucleus during quiescence. The Journal of Cell Biology 203(4): 585-594.
12. Evertts AG, Manning AL, Wang X, Dyson NJ, Garcia BA, et al. (2013) H4K20 methylation regulates quiescence and chromatin compaction. Molecular Biology of the Cell 24(19): 3025-3037.
13. Yusuf I, Fruman DA (2003) Regulation of quiescence in lymphocytes. Trends in Immunology 24(7): 380-386.
14. Gray JV, Petsko GA, Johnston GC, Ringe D, Singer RA, et al. (2004) "Sleeping Beauty": Quiescence in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 68(2): 187-206.
15. Coller HA, Sang L, Roberts JM (2006) A New Description of Cellular Quiescence. PLoS Biol 4(3): E83.
16. Ekholm SV, Reed SI (2000) Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle. Current Opinion in Cell Biology 12(6): 676-684.
17. Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes & Development 18(22): 2699-2711.
18. Perucca P, Cazzalini O, Madine M, Savio M, Laskey RA, et al. (2009) Loss of p21(CDKN1A) impairs entry to quiescence and activates a DNA damage response in normal fibroblasts induced to quiescence. Cell Cycle 8(1): 105-114.
19. Brown JP, Wei W, Sedivy JM (1997) Bypass of Senescence After Disruption of p21CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts. Science 277(5327): 831-834.
20. Herbig U, Jobling WA, Chen BPC, Chen DJ, Sedivy JM (2004) Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a. Molecular Cell 14(4): 501-513.
21. Jiang H, Lin J, Su Z, Collart F, Huberman E, et al. (1994) Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21waf1cip1 expression in the absence of p53. Oncogene 9: 3397-3406.
22. Zezula J, Casaccia-Bonnefil P, Ezhevsky SA, Osterhout DJ, Levine JM, et al. (2001) p21cip1 is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal pp 27-34.
23. Rivard N, L'Allemain G, Bartek J, Pouysségur J (1996) Abrogation of p27Kip1 by cDNA Antisense Suppresses Quiescence (G0 State) in Fibroblasts. Journal of Biological Chemistry 271(31): 18337- 18341.
24. Ladha MH, Lee KY, Upton TM, Reed MF, Ewen ME (1998) Regulation of Exit from Quiescence by p27 and Cyclin D1-CDK4. Molecular and Cellular Biology 18(11): 6605-6615.
25. Sgambato A, Cittadini A, Faraglia B, Weinstein IB (2000) Multiple functions of p27Kip1 and its alterations in tumor cells: A review. Journal of Cellular Physiology 183(1): 18-27.
26. Chassot AA, Lossaint G, Turchi L, Meneguzzi G, Fisher D, et al. (2008) Confluence-induced cell cycle exit involves pre-mitotic CDK inhibition by p27Kip1 and cyclin D1 downregulation. Cell Cycle 7(13): 2038-2046.
27. Sang L, Coller HA, Roberts JM (2008) Control of the Reversibility of Cellular Quiescence by the Transcriptional Repressor HES1. Science 321(5892): 1095-1100.
28. Munro J, Steeghs K, Morrison V, Ireland H, Parkinson EK (2001) Human fibroblast replicative senescence can occur in the absence of extensive cell division and short telomeres. Oncogene 20: 3541-3552.
29. Hayflick L, Moorhead P (1961) The serial cultivation of human diploid cell strains. Experimental Cell Research 25: 585-621.
30. Krtolica A, Campisi J (2002) Cancer and aging: A model for the cancer promoting effects of the aging stroma. The International Journal of Biochemistry & Cell Biology 34: 1401-1414.
31. Hayflick L (1985) Theories of biological aging. Experimental Gerontology 20: 145-159.
32. Sager R (1991) Senescence as a mode of tumor suppression. Environ. Health Perspect 93: 59-62.
33. Hornsby PJ (2002) Cellular Senescence and Tissue Aging In Vivo. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57(7): B251-B256.
34. Campisi J (2005) Suppressing Cancer: The Importance of Being Senescent. Science 309(5736): 886- 887.
35. Adams PD (2009) Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence. Molecular Cell 36(1): 2-14.
36. Ben-Porath I, Weinberg RA (2004) When cells get stressed: An integrative view of cellular senescence. The Journal of Clinical Investigation 113(1): 8-13.
37. Cristofalo VJ, Lorenzini A, Allen RG, Torres C, Tresini M (2004) Replicative senescence: A critical review. Mechanisms of Ageing and Development 125(10-11): 827-848.
38. Dimri GP, Lee X, Basile G, Acosta M, Scott G, et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences 92(20): 9363-9367.
39. Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53- dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes & Development 8(21): 2540-2551.
40. Bladier C, Wolvetang E, Hutchinson P, de Haan J, Kola I (1997) Response of a primary human fibroblast cell line to H2O2: Senescence-like growth arrest or apoptosis? Cell Growth Differ 8(5): 589- 598.
41. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a. Cell 88(5): 593-602.
42. Toussaint O, Medrano EE, von Zglinicki T (2000) Cellular and molecular mechanisms of stressinduced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Experimental Gerontology 35(8): 927-945.
43. Debacq-Chainiaux F, Borlon C, Pascal T, Royer V, Eliaers F, et al. (2005) Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF-b1 signaling pathway. Journal of Cell Science 118(4): 743-758.
44. Mallette FA, Gaumont-Leclerc MF, Ferbeyre G (2007) The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes & Development 21(1): 43-48.
45. Dimri GP, Itahana K, Acosta M, Campisi J (2000) Regulation of a Senescence Checkpoint Response by the E2F1 Transcription Factor and p14ARF Tumor Suppressor. Molecular and Cellular Biology 20(1): 273-285.
46. Pearson M, Carbone R, Sebastiani C, Cioc M, Fagioli M, et al. (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406(6792): 207-210.
47. Ben-Porath I, Weinberg RA (2005) The signals and pathways activating cellular senescence. The International Journal of Biochemistry & Cell Biology 37(5): 961-976.
48. Zglinicki Tv, Saretzki G, Ladhoff J, Fagagna FdAd, Jackson SP (2005) Human cell senescence as a DNA damage response. Mechanisms of Ageing and Development 126(1): 111-117.
49. Campisi J, d'Adda di Fagagna F (2007) Cellular senescence: When bad things happen to good cells. Nat Rev Mol Cell Biol 8(9): 729-740.
50. Steinert S, Shay JW, Wright WE (2000) Transient Expression of Human Telomerase Extends the Life Span of Normal Human Fibroblasts. Biochemical and Biophysical Research Communications 273(3): 1095-1098.
51. Hemann MT, Strong MA, Hao LY, Greider CW (2001) The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability. Cell 107(1): 67-77.
52. de Lange T (2002) Protection of mammalian telomeres. Oncogene 21: 532-540.
53. Campisi J (2008) Aging and cancer cell biology, 2008. Aging Cell 7(3): 281-284.
54. Sedelnikova OA, Horikawa I, Zimonjic D, Popescu N, Bonner W, et al. (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6(2): 168-170.
55. Hwang ES (2002) Replicative senescence and senescence-like state induced in cancer-derived cells. Mechanisms of Ageing and Development 123(12): 1681-1694.
56. Gire V, Wynford-Thomas D (1998) Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies. Molecular and Cellular Biology 18(3): 1611- 1621.
57. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, et al. (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways pp 4212-4222.
58. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z, et al. (2010) Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence. Cancer Cell 17(4): 376-387.
59. Hara E, Smith R, Parry D, Tahara H, Stone S, et al. (1996) Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Molecular and Cellular Biology 16(3): 859-867.
60. Mazars GR, Jat PS (1997) Expression of p24, a novel p21Waf1/Cip1/Sdi1-related protein, correlates with measurement of the finite proliferative potential of rodent embryo fibroblasts. Proceedings of the National Academy of Sciences 94(1): 151-156.
61. Jones CJ, Kipling D, Morris M, Hepburn P, Skinner J, et al. (2000) Evidence for a Telomere- Independent "Clock" Limiting RAS Oncogene-Driven Proliferation of Human Thyroid Epithelial Cells. Molecular and Cellular Biology 20(15): 5690-5699.
62. Durand B, Gao FB, Raff M (1997) Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation pp 306-317.
63. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The Hallmarks of Aging. Cell 153(6): 1194-1217.
64. Harley CB (1991) Telomere loss: mitotic clock or genetic time bomb? Mutation Research/DNAging 256(2-6): 271-282.
65. Cristofalo VJ, Pignolo RJ (1993) Replicative senescence of human fibroblast like cells in culture. Physiological Reviews 73(3): 617-638.
66. Lorenzini A, Johnson FB, Oliver A, Tresini M, Smith JS, et al. (2009) Significant correlation of species longevity with DNA double strand break-recognition but not with telomere length. Mech. Ageing Dev 130: 784-792.
67. Wright WE, Shay JW (2001) Cellular senescence as a tumor-protection mechanism: The essential role of counting. Current Opinion in Genetics & Development 11: 98-103.
68. Severino J, Allen RG, Balin S, Balin A, Cristofalo VJ (2000) Is b Galactosidase Staining a Marker of Senescence in Vitro and in Vivo? Experimental Cell Research 257(1): 162-171.
69. Yang NC, Hu ML (2005) The limitations and validities of senescence associated-b galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Experimental Gerontology 40(10): 813-819.
70. Cristofalo VJ (2005) SA b Gal staining: Biomarker or delusion. Experimental Gerontology 40(10): 836- 838.
71. Cho S, Hwang E (2012) Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells 33(6): 597-604.
72. Imai Y, Takahashi A, Hanyu A, Hori S, Sato S, et al. (2014) Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch. Cell Reports 7(1): 194-207.
73. Lane AA, Scadden DT (2010) Stem Cells and DNA Damage: Persist or Perish? Cell 142(3): 360-362.
74. Crescenzi E, Palumbo G, Brady HJM (2003) Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J 375(2): 263-274.
75. Ashrafi K, Sinclair D, Gordon JI, Guarente L (1999) Passage through stationary phase advances replicative ageing in S. cerevisiae. Proceedings of the National Academy of Sciences USA 96: 9100- 9105.
76. Lucibello FC, Sewing A, Brusselbach S, Burger C, Muller R (1993) Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. Journal of Cell Science 105(1): 123- 133.
77. Atadja P, Wong H, Veillete C, Riabowol K (1995) Overexpression of Cyclin D1 Blocks Proliferation of Normal Diploid Fibroblasts. Experimental Cell Research 217(2): 205-216.
78. Meyyappan M, Wong H, Hull C, Riabowol KT (1998) Increased Expression of Cyclin D2 during Multiple States of Growth Arrest in Primary and Established Cells. Molecular and Cellular Biology 18(6): 3163-3172.
79. Schauble S, Klement K, Marthandan S, Munch S, Heiland I, et al. (2012) Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts. Plos One 7: E42150.
80. Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, et al. (2000) A critical role for histone H2A.X in recruitment of repair factors to nuclear foci after DNA damage. Current Biology 10(15): 886- 895.
81. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM Phosphorylates Histone H2A.X in Response to DNA Double-strand Breaks. Journal of Biological Chemistry 276(45): 42462-42467.
82. Lowndes NF, Toh GWL (2005) DNA Repair: The Importance of Phosphorylating Histone H2A.X. Current Biology 15(3): R99-R102.
83. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U (2007) Accumulation of senescent cells in mitotic tissue of aging primates. Mechanisms of Ageing and Development 128(1): 36-44.
84. Kouzarides T (2007) Chromatin Modifications and Their Function. Cell 128(4): 693-705.
85. Sitte N, Saretzki G, von Zglinicki T (1998) Accelerated Telomere Shortening in Fibroblasts After Extended Periods of Confluency. Free Radical Biology and Medicine 24(6): 885-893.
86. Parrinello S, Samper E, Krtolica A, Goildstein J, Melov S, et al. (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5(8): 741-747.
87. Forsyth NR, Evans AP, Shay JW, Wright WE (2003) Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell 2: 235-243.
88. Pitiyage GN, Slijepcevic P, Gabrani A, Chianea YG, Lim KP, et al. (2011) Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases. Journal of Pathology 223: 604-617.
89. Atamna H, Paler-Martinez A, Ames BN (2000) N-t-butyl hydroxylamine, a hydrolysis product of alphaphenyl- N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts. Journal of Biologiocal Chemistry 275: 6741-6748.
90. Forsyth NR, Wright WE, Shay JW (2002) Telomerase and differentiation in multicellular organisms: Turn it off, turn it on, and turn it off again. Differentiation 69(4-5): 188-197.
91. Seluanov A, Gorbunova V, Falcovitz A, Siqal A, Milyavsky M, et al. (2001) Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53. Molecular and Cellular Biology 21(5): 1552-1564.
92. Manns J, Daubrawa M, Driessen S, Paasch F, Hoffmann N, et al. (2011) Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: Activation of caspase-9 in the absence of Apaf- 1. The FASEB Journal 25(9): 3250-3261.
93. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1999) Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL. Journal of Biological Chemistry 274(4): 2225-2233.
94. Pawlowski J, Kraft AS (2000) Bax-induced apoptotic cell death. Proceedings of the National Academy of Sciences 97(2): 529-531.
95. Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55: 2284-2292.
96. Naderi J, Hung M, Pandey S (2003) Oxidative stress-induced apoptosis in dividing fibroblasts involves activation of p38 MAP kinase and over-expression of Bax: resistance of quiescent cells to oxidative stress. Apoptosis 8: 91-100.
97. Lackner DH, Hayashi MT, Cesare AJ, Karlseder J (2014) A genomics approach identifies senescencespecific gene expression regulation. Aging Cell 2014 May 23. doi: 10.1111/acel.12234. [Epub ahead of print].
98. Augenlicht LH, Baserga R (1974) Changes in the Go state of WI-38 fibroblasts at different times after confluence. Exp Cell Res 89: 255-262.
99. Soprano KJ (1994) WI-38 cell long term quiescence model system. A valuable tool to study molecular events that regulate growth. Journal of Cellular Biochemistry 54(4): 405-414.
100. Pignolo RJ, Martin BG, Horton JH, Kalbach AN, Cristofalo VJ (1998) The Pathway of Cell Senescence: WI-38 Cells Arrest in Late G1 and Are Unable to Traverse the Cell Cycle from a True G0 State. Experimental Gerontology 33(1-2): 67-80.
101. Beerman I, Seita J, Inlay Matthew A, Weissman Irving L, Rossi Derrick J (2014) Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle. Cell Stem Cell 15(1): 37-50.
102. Wolstein JM, Lee DH, Michaud J, Buot V, Stefanchik B, et al. (2010) INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction pp F1486- F1495.
103. Zhang X, Wu X, Tang W, Luo Y (2012) Loss of p16 (Ink4a) function rescues cellular senescence induced by telomere dysfunction. Int J Mol Sci 13: 5866-5877.
104. Okamoto A, Demetrick DJ, Spillare EA, Hagiwara K, Hussain SP, et al. (1994) Mutations and altered expression of p16INK4 in human cancer. Proceedings of the National Academy of Sciences 91(23): 11045-11049.
105. Serrano M, Lee HW, Chin L, Carlos-Cardo C, Bleach D, et al. (1996) Role of the INK4a Locus in Tumor Suppression and Cell Mortality. Cell 85(1): 27-37.
106. Uhrbom L, Nister M, Westermark B (1997) Induction of senescence in human malignant glioma cells by p16INK4a. Oncogene 15: 505-514.
107. Dai CY, Enders GH (2000) p16 INK4a can initiate an autonomous senescence program. Oncogene 19: 1613-1622.
108. DeJesus V, Rios I, Davis C, Chen Y, Calhoun D, et al. (2002) Induction of apoptosis in human replicative senescent fibroblasts. Exp. Cell Res 274: 92-99.
109. Zhang J, Patel JM, Block ER (2002) Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. Mech. Ageing Dev 123: 613-625.
110. Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk. SSSR 201: 1496-1499.
111. Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239: 197-201.
112. Saretzki G, Sitte N, Merkel U, Wurm RE (1999) Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments. Oncogene 18: 5148-5158.
113. Shiloh Y (2006) The ATM-mediated DNA-damage response: Taking shape. Trends in Biochemical Sciences 31(7): 402-410.
114. Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, et al. (1995) Telomere Shortening Is Associated with Cell Division in Vitro and in Vivo. Experimental Cell Research 220(1): 194- 200.
115. Smith JR, Whitney RG (1980) Intraclonal variation in proliferative potential of human diploid fibroblasts: Stochastic mechanism for cellular aging. Science 207: 82-84.
116. Suram A, Herbig U (2014) The replicometer is broken: Telomeres activate cellular senescence in response to genotoxic stresses. Aging Cell 13: 780-786.
117. Bodnar AG, Quellette M, Frolkis M, Holt SE, Chiu CP, et al. (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352.
118. Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9(2): 81-94.
119. Passos J, Simillion C, Hallinan J, Wipat A, von Zglinicki T (2009) Cellular senescence: unravelling complexity. AGE 31(4): 353-363.
120. Thuret G, Chiquet C, Herrag S, Dumollard JM, Boudard D, et al. (2003) Mechanisms of staurosporine induced apoptosis in a human corneal endothelial cell line. British Journal of Ophthalmology 87(3): 346- 352.
121. Johansson AC, Steen H, Ollinger K, Roberg K (2003) Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine. Cell Death Differ 10(11): 1253-1259.
122. Kim S, Ryu S, Kang H, Choi H, Park S (2011) Defective nuclear translocation of stress-activated signaling in senescent diploid human fibroblasts: A possible explanation for aging-associated apoptosis resistance. Apoptosis 16(8): 795-807.
123. Soldani C, Bottone MG, Pellicciari C, Scovassi AI (2001) Two-color fluorescence detection of Poly (ADP-Ribose) Polymerase-1 (PARP-1) cleavage and DNA strand breaks in etoposide-induced apoptotic cells. Eur J Histochem 45: 389-392.
124. Mazzini G, Ferrari C, Erba E (2003) Dual excitation multi-fluorescence flow cytometry for detailed analyses of viability and apoptotic cell transition. Europ J Histochem 47: 289-298.
125. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, et al. (2013) TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14(4): R36.
126. Liao Y, Smyth GK, Shi W (2014) featureCounts: An efficient general purpose program for assigning sequence reads to genomic features." Bioinformatics (Oxford, England) 30(7): 923-930.
127. Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106.
128. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139-140.
129. Hardcastle TJ, Kelly KA (2010) bay Seq: Empirical Bayesian methods for identifying differential expression in sequence count data. BMC Bioinformatics 11: 422.
130. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, Series B 57(1): 289-300.
131. Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nature Protoc 4(1): 44-57.
132. Luo W, Friedman MS, Shedden K, Hankenson KD, Woolf PJ (2009) GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinformatics 10: 161.
133. Holliday R (2014) The commitment of human cells to senescence. Interdiscip Top Gerontol. 39: 1-7.
134. Jacobs JP, Jones CM, Baille JP (1970) Characteristics of a human diploid cell designated MRC-5. Nature 227(5254): 168-170.
135. Trlifjova J, Strizova V, Trlifaj L, Budsinsky Z, Fruhbauer Z (1968) A prolonged cultivation of the human diploid cell strain WI-38. J Hyg Epidemiol Microbiol Immunol 12(2): 212-226.