Role of the ataxia telangiectasia mutated protein in stress-induced premature senescence

Ataxia: Causes, Symptoms and Treatment

Volumn , Issue , 2012, Pages 1-27

  Mirzayans, Razmik ^a   Murray, David ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

Ataxia telangiectasia; DNA damage response; Ionizing radiation; Senescence

Indexed keywords

EID: 84864932631     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (162)

1. Adams, K. E., Medhurst, A. L., Dart, D. A. & Lakin, N. D. (2006). Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex. Oncogene, 25, 3894-3904.
2. Afshar, G., Jelluma, N., Yang, X., Basila, D., Arvold, N. D., Karlsson, A., Yount, G. L., Dansen, T. B., Koller, E. & Haas-Kogan, D. A. (2006). Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells. Cancer Res., 66, 4223-4232.
3. Akhtar, R. S., Geng, Y., Klocke, B. J., Latham, C. B., Villunger, A. W., Michalak, E. M., Strasser, A., Carroll, S. L. & Roth, K. A. (2006). BH3-Only proapoptotic Bcl-2 family members Noxa and Puma mediate neural precursor cell death. J. Neurosci., 26, 7257-7264.
4. Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D. & Barrett, J. C. (1996). Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl. Acad. Sci. USA, 93, 13742-13747.
5. Al-Mohanna, M. A., Manogaran, P. S., Al-Mukhalafi, Z. A., Al-Hussein, K. & Aboussekhra, A. (2004). The tumor suppressor p16INK4a gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Oncogene, 23, 201-212.
6. Al Rashid, S. T., Dellaire, G., Cuddihy, A., Jalali, F., Vaid, M., Coackley, C., Folkard, M., Xu, Y., Chen, B. P., Chen, D. J., Lilge, L., Prise, K. M., Bazett-Jones, D. P. & Bristow, R. G. (2005). Evidence for the direct binding of phosphorylated p53 to sites of DNA breaks in vivo. Cancer Res., 65, 10810-10821.
7. Ammazzalorso, F., Pirzio, L. M., Bignami, M., Franchitto, A. & Pichierri, P. (2010). ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J., 29, 3156-3169.
8. Asada, M., Yamada, T., Ichijo, H., Delia, D., Miyazono, K., Fukumuro, K. & Mizutani, S. (1999). Apoptosis inhibitory activity of cytoplasmic p21Cip1/WAF1 in monocytic differentiation. EMBO J., 18, 1223-1234.
9. Batchelor, E., Mock, C. S., Bhan, I., Loewer, A. & Lahav, G. (2008). Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol. Cell, 9, 277-289.
10. Bakkenist, C. J. & Kastan, M. B. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421, 499-506.
11. Barley, R. D. C., Enns, L., Paterson, M. C. & Mirzayans, R. (1998). Aberrant p21WAF1-dependent growth arrest as the possible mechanism of abnormal resistance to ultraviolet light cytotoxicity in Li-Fraumeni syndrome fibroblast strains heterozygous for TP53 mutations. Oncogene, 17, 533-543.
12. Baylin, S. B. (1997). Tying it all together: epigenetics, genetics, cell cycle, and cancer. Science, 277, 1948-1949.
13. Bensimon, A., Aebersold, R. & Shiloh, Y. (2011). Beyond ATM: the protein kinase landscape of the DNA damage response. FEBBS Lett., 585, 1625-1639.
14. Bhatia, P., Menigatti, M., Brocard, M., Morley, S. J. & Ferrari, S. (2010). Mitotic DNA damage targets the Aurora A/TPX2 complex. Cell Cycle, 9, 4592-4599.
15. Bond, J., Jones, C., Haughton, M., DeMicco, C., Kipling, D. & Wynford-Thomas, D. (2004). Direct evidence from siRNA-directed "knock down" that p16INK4a is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation. Exp. Cell Res., 292, 151-156.
16. Brookes, S., Rowe, J., Gutierrez Del Arroyo, A., Bond, J. & Peters, G. (2004). Contribution of p16INK4a to replicative senescence of human fibroblasts. Exp. Cell Res., 298, 549-559.
17. Brown, K. D., Barlow, C. & Wynshaw-Boris, A. (1999). Multiple ATM-dependent pathways: an explanation for pleiotropy. Am. J. Hum. Genet., 64, 46-50.
18. Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W. & Vogelstein, B. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science, 282, 1497-501.
19. Burma, S. & Chen, D. J. (2004). Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (Amst.), 3, 909-918.
20. Chan, S. W. & Blackburn, E. H. (2003). Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol. Cell, 11, 1379-1387.
21. Chang, B. D., Broude, E. V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y., Kandel, E. S., Lausch, E., Christov, K. & Roninson, I. B. (1999a). A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res., 59, 3761-3767.
22. Chang, B. D., Xuan, Y., Broude, E. V., Zhu, H., Schott, B., Fang, J. & Roninson, I. B. (1999b). Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene, 15, 4808-4818.
23. Chang, B. D., Watanabe, K., Broude, E. V., Fang. J., Poole, L. C., Kalinchenko, T. & Roninson, I. B. (2000). Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases. Proc. Natl. Acad. Sci. USA, 97, 4291-4296.
24. Chen, Q. M., Prowse, K. R., Tu, V. C., Purdom, S. & Linskens, M. H. (2001). Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Exp. Cell Res., 265, 294-303.
25. Chen, L., Huang, S., Lee, L., Davalos, A., Schiestl, R. H., Campisi, J. & Oshima, J. (2003). WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging Cell, 2, 191-199.
26. Chen, C. R., Wang, W., Rogoff, H. A., Xiaotong, L., Mang, W. & Li, C. J. (2005). Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. Cancer Res., 65, 6017-6021.
27. Chen, B. P., Uematsu, N., Kobayashi, J., Lerenthal, Y., Krempler, A., Yajima, H., Löbrich, M., Shiloh, Y. & Chen, D. J. (2007). Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J. Biol. Chem., 282, 6582-6587.
28. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. (1994). Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science, 265, 346-355.
29. Chuang, L., Ian, H. I., Koh, T. W., Ng, H. H., Xu, G. & Li, B. F. (1997). Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science, 277, 1996-2000.
30. Cook, J. G. (2009). Replication licensing and the DNA damage checkpoint. Front. Biosci., 14, 5013-5030.
31. Corroyer, S., Nabeyrat, E. & Clement, A. (1997). Involvement of the cell cycle inhibitor CIP1/WAF1 in lung alveolar epithelial cell growth arrest induced by glucocorticoids. Endocrinology, 138, 3677-3685.
32. Costanzo, V., Paull, T., Gottesman, M. & Gautier, J. (2004). Mre11 assembles linear DNA fragments into DNA damage signaling complexes. PLoS Biol., 2, E110.
33. Crescenzi, E., Palumbo, G., de Boer, J. & Brady, H. J. (2008). Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clin. Cancer Res., 14, 1877-1887.
34. Cristofalo, V. J. & Pignolo, R. J. (1993). Replicative senescence of human fibroblast-like cells in culture. Physiol. Rev., 73, 617-638.
35. Cuadrado, M., Martinez-Pastor, B., Murga, M., Toledo, L. I,, Gutierrez-Martinez, P., Lopez, E. & Fernandez-Capetillo, O. (2006). ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J. Exp. Med., 203, 297-303.
36. Datto, M. B., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y. & Wang, X. F. (1995). Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. Sci., USA, 92, 5545-5549.
37. De Leong, W. F., Chau, J. F. L. & Li, B. (2009). p53 deficiency leads to compensatory up-regulation of p16INK4a. Mol. Cancer Res., 7, 354-360.
38. Delavaine, L. & La Thangue, N. B. (1999). Control of E2F activity by p21Waf1/Cip1. Oncogene, 18, 5381-5392.
39. di Fagagna, F. d'A., Reaper, P. M., Clay-Farrace, L., Fiegler H., Carr P., von Zglinicki, T., Saretzki G., Carter N. P. & Jackson S. P. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426, 194-198.
40. DiBiase, S. J., Guan, J., Curran, W. J. & Iliakis, G. (1999). Repair of DNA double-strand breaks and radiosensitivity to killing in an isogenic group of p53 mutant cell lines. Int. J. Radiat. Oncol. Biol. Phys., 45, 743-751.
41. Dickson, M. A., Hahn, W. C., Ino, Y., Ronfard, V., Wu, J. Y., Weinberg, R. A., Louis, D. N., Li, F. P. & Rheinwald, J. G. (2000). Human keratinocytes that express hTERT and also bypass a p16INK4a-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol. Cell. Biol., 20, 1436-1447.
42. El Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W. & Vogelstein, B. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75, 817-825.
43. Enoch, T. & Norbury, C. (1995). Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem. Sci., 20, 426-430.
44. Enns, L., Barley, R. D., Paterson, M. C. & Mirzayans, R. (1998). Radiosensitivity in ataxia telangiectasia fibroblasts is not associated with deregulated apoptosis. Radiat. Res., 150, 11-16.
45. Enns, L., Murray, D. & Mirzayans, R. (1999). Effects of the protein kinase inhibitors wortmannin and KN62 on cellular radiosensitivity and radiation-activated S phase and G1/S checkpoints in normal human fibroblasts. Br. J. Cancer, 81, 959-965.
46. Erenpreisa, J. & Cragg, M. S. (2001). Mitotic death: a mechanism of survival? A review. Cancer Cell Int., 1, 1-7.
47. Erenpreisa, J., Ivanov, A., Wheatley, S. P., Kosmacek, E. A., Ianzini, F., Anisimov, A. P., Mackey, M., Davis, P. J., Plakhins. G. & Illidge, T. M. (2008). Endopolyploidy in irradiated p53-deficient tumour cell lines: persistence of cell division activity in giant cells expressing Aurora-B kinase. Cell. Biol. Int., 32, 1044-1056.
48. Erenpreisa, J., Cragg, M. S., Salmina, K., Hausmann, M. & Scherthan, H. (2009). The role of meiotic cohesin REC8 in chromosome segregation in γ irradiation-induced endopolyploidtumour cells. Exp. Cell Res., 315, 2593-2603.
49. Fernandez-Capetillo, O., Lee, A., Nussenzweig, M. & Nussenzweig, A. (2004). H2AX: the histone guardian of the genome. DNA Repair (Amst.), 3, 959-967
50. Ford, J. M. (2005). Regulation of DNA damage recognition and nucleotide excision repair: another role for p53. Mutat. Res., 577, 195-202.
51. Freedman, D. A. & Folkman, J. (2004). CDK2 translational down-regulation during endothelial senescence. Exp. Cell Res., 307, 118-130.
52. Fuster, J. J., Sanz-González, S. M., Moll, U. M. & Andres, V. (2007). Classic and novel roles of p53: prospects for anticancer therapy. Trends Mol. Med., 13, 192-199.
53. Gatti, R. A., Boder, E., Vinters, H. V., Sparkes, R. S., Norman, A. & Lange, K. (1991). Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine, 70, 99-117.
54. Gewirtz, D. A., Holt, S. E. & Elmore, L. W. (2008). Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem. Pharmacol., 76, 947-957.
55. Gillis, L. D., Leidal, A. M., Hill, R. & Lee, P. W. (2009). p21Cip1/WAF1 mediates cyclin B1 degradation in response to DNA damage. Cell Cycle, 8, 253-256.
56. Goodarzi, A. A., Noon, A. T., Deckbar, D., Ziv, Y., Shiloh, Y., Löbrich, M. & Jeggo, P. A. (2008). ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell, 31, 167-177.
57. Gu, Y., Turck, C. W. & Morgan, D. O. (1993). Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature, 366, 707-710.
58. Guo, C. Y., D'Anna, J. A., Li, R. & Larner, J. M. (1999). The radiation-induced S-phase checkpoint is independent of CDKN1A. Radiat. Res., 151, 125-965.
59. Haff, R. F. & Swim, H. E. (1956). Serial propagation of 3 strains of rabbit fibroblasts: their susceptibility to infection with vaccinia virus. Proc. Soc. Exp. Biol. Med., 93, 200-204.
60. Han, Z., Wei, W., Dunaway, S., Darnowski, J. W., Calabresi, P., Sedivy, J., Hendrickson, E. A., Balan, K. V., Pantazis, P. & Wyche, J. H. (2002). Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J. Biol. Chem., 277, 17154-17160.
61. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 75, 805-816.
62. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. (2004). Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell, 14, 501-513.
63. Hernández-Vargas, H., Ballestar, E., Carmona-Saez, P., von Kobbe, C., Bañón-Rodríguez, I., Esteller, M., Moreno-Bueno, G. & Palacios, J. (2006). Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int. J. Cancer, 119, 1164-1175.
64. Horejsi, Z., Falck, J., Bakkenist, C. J., Kastan, M. B., Lukas, J. & Bartek, J. (2004). Distinct functional domains of Nbs1 modulate the timing and magnitude of ATM activation after low doses of ionizing radiation. Oncogene, 23, 3122-3127.
65. Hu, P. P., Shen, X., Huang, D., Liu, Y., Counter, C. & Wang, X. F. (1999). The MEK pathway is required for stimulation of p21WAF1/CIP1 by transforming growth factor-beta. J. Biol. Chem., 274, 35381-35387.
66. Ianzini, F., Kosmacek, E. A., Nelson, E. S., Napoli, E., Erenpreisa, J., Kalejs, M. & Mackey, M. A. (2009). Activation of Meiosis-Specific Genes Is Associated with Depolyploidization of Human Tumor Cells following Radiation-Induced Mitotic Catastrophe. Cancer Res., 69, 2296-2304.
67. Illidge, T. M., Cragg, M. S., Fringes, B., Olive, P. & Erenpresia, J. A. (2000). Polyploid giant cells provide a survival mechanism of p53 mutant cells after DNA damage. Cell Biol. Int., 24, 621-633.
68. Itahana, K., Zou, Y., Itahana, Y., Martinez, J. L., Beausejour, C., Jacobs, J. J., Van Lohuizen, M., Band, V., Campisi, J. & Dimri, G. P. (2003). Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol., 23, 389-401.
69. Jacobs, J. J. & de Lange, T. (2005). p16INK4a as a second effector of the telomere damage pathway. Cell Cycle, 4, 1364-1368.
70. Javelaud, D. & Besançon, F. (2002). Inactivation of p21WAF1 sensitizes cells to apoptosis via an increase of both p14ARF and p53 levels and an alteration of the Bax/Bcl-2 ratio. J. Biol. Chem., 277, 37849-37954.
71. Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C., Lukas, J. & Jackson, S. P. (2006). ATM-and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell Biol., 8, 37-45.
72. Jiang, H., Lin, J., Su, Z. Z., Herlyn, M., Kerbel, R. S., Weissman, B. E, Welch, D. R. & Fisher, P. B. (1995). The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene, 10, 1855-1864.
73. Jongmans, W., Vuillaume, M., Kleijer, W. J., Lakin, N. D. & Hall J. (1998). The p53-mediated DNA damage response to ionizing radiation in fibroblasts from ataxia-without-telangiectasia patients. Int. J. Radiat. Biol., 74, 287-295.
74. Kato, D., Miyazawa, K., Ruas, M., Starborg, M., Wada, I., Oka, T., Sakai, T., Peters, G. & Hara, E. (1998). Features of replicative senescence induced by direct addition of antennapedia-p16Ink4A fusion protein to human diploid fibroblasts. FEBS Lett., 427, 203-208.
75. Kato, T. A., Nagasawa, H., Weil, M. M., Genik, P. C., Little, J. B. & Bedford, J. S. (2006). γ-H2AX foci after low-dose-rate irradiation reveal atm haploinsufficiency in mice. Radiat. Res., 166, 47-54.
76. Khanna, K. K. (2000). Cancer risk and the ATM gene: a continuing debate. JNCI, 92, 795-802.
77. Kitaura, H., Shinshi, M., Uchikoshi, Y., Ono, T., Iguchi-Ariga, S. M. & Ariga, H. (2000). Reciprocal regulation via protein-protein interaction between c-Myc and p21cip1/waf1/sdi1 in DNA replication and transcription. J. Biol. Chem., 275, 10477-10483.
78. Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A. &. Klingelhutz, A. J. (1998). Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature, 396, 84-88.
79. Kühne, M., Riballo, E., Rief, N., Rothkamm, K., Jeggo, P. A. & Löbrich, M. (2004). A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res., 64, 500-508.
80. Kurz, E. U. & Lees-Miller, S. P. (2004). DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair, 3, 889-900.
81. Lahav, G., Rosenfeld, N., Sigal, A., Geva-Zatorsky, N., Levine, A. J., Elowitz, M. B. & Alon, U. (2008). Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat. Genet., 36, 147-150.
82. Lane, D. P. (2004). p53 from pathway to therapy. Carcinogenesis, 25, 1077-1081.
83. Lau, W. M., Ho, T. H. & Hui, K. M. (2007). p16INK4A-silencing augments DNA damage-induced apoptosis in cervical cancer cells. Oncogene, 26, 6050-6060.
84. Lavin, M. F. (2008). Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell Biol. 9, 759-769.
85. Lavin, M. F. & Khanna, K. K. (1999). ATM: the protein encoded by the gene mutated in the radiosensitive syndrome ataxia-telangiectasia. Int. J. Radiat. Biol., 75, 1201-1214.
86. Lavin, M. F., Gueven, N., Bottle, S. & Gatti, R. A. (2007). Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br. Med. Bull., 81-82, 129-147.
87. Le, H. V., Minn, A. J. & Massague, J. (2005). Cyclin-dependent kinase inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells. J. Biol. Chem., 280, 32018-32025.
88. Li, C. Y., Suardet, L. & Little, J. B. (1995). Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. J. Biol. Chem., 270, 4971-4974.
89. Li, M., Luo, J., Brooks, C. L. & Gu, W. (2002). Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem., 277, 50607-50611.
90. Li, Q., Zhao, L. Y., Zheng, Z., Yang, H., Santiago, A. & Liao, D. (2011). Inhibition of p53 by adenovirus type 12 E1B-55K deregulates cell cycle control and sensitizes tumor cells to genotoxic agents. J. Virol., 85, 7976-7988.
91. Liu, M., Iavarone, A. & Freedman, L. P. (1996). Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor. Correlation with retinoid induction of U937 cell differentiation. J. Biol, Chem., 271, 31723-31728.
92. Liu, J., Song, Y., Qian, J., Liu, B., Dong, Y., Tian, B. & Sun, Z. (2011). Promyelocytic leukemia protein interacts with werner syndrome helicase and regulates double-strand break repair in γ-irradiation-induced DNA damage responses. Biochemistrey (Mosc.), 76, 550-554.
93. Ljungman, M. (2000). Dial 9-1-1 for p53: Mechanisms of p53 activation by cellular stress. Neoplasia, 2, 208-225.
94. Mansilla, S., Bataller, M. & Portugal, J. (2009). A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells. Biochem. Pharmacol., 78, 123-132.
95. McConnell, B. B., Starborg, M., Brookes, S. & Peters, G. (1998). Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr. Biol., 8, 351-354.
96. Meek, D. W. (2004). The p53 response to DNA damage. DNA Repair, 3, 1049-1056.
97. Meulmeester, E., Pereg, Y., Shiloh, Y. & Jochemsen, A. G. (2005). ATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation. Cell Cycle, 4, 1166-1170.
98. Meyn, M. S. (1995). Ataxia-telangiectasia and cellular response to DNA damage. Cancer Res., 55, 5991-6001.
99. Michael, D. & Oren, M. (2003). The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol., 13, 49-58.
100. Mirzayans, R. & Murray, D. (1997). Cellular senescence: Implications for cancer therapy. In: Garvey RB Ed. New Research on Cell Aging. Hauppauge, NY, Nova Science Publishers, Inc.; pp. 1-64.
101. Mirzayans, R. & Paterson, M. C. (1991). Lack of correlation between hypersensitivity to cell killing and impaired inhibition of DNA synthesis in ataxia telangiectasia fibroblasts treated with 4-nitroquinoline 1-oxide. Carcinogenesis, 12, 19-24.
102. Mirzayans, R. & Paterson, M. C. (2001). Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment. Environ. Mol. Mutagen., 38, 191-199.
103. Mirzayans, R., Sabour, M. & Paterson, M. C. (1988). Enhanced bioreduction of 4-mtroquinoline 1-oxide by cultured ataxia telangiectasia cells. Carcinogenesis, 9, 1711-1715.
104. Mirzayans, R., Smith, B. P. & Paterson, M. C. (1989). Hypersensitivity to cell killing and faulty repair of 1--D-arabinofuranosylcytosine-detectable sites in human (ataxia-telangiectasia) fibroblasts treated with 4-nitroquinoline 1-oxide. Cancer Res., 49, 5523-5529.
105. Mirzayans, R., Famulski, K., Enns, L., Fraser, M. & Paterson, M. C. (1995). Characterization of the signal transduction pathway mediating γ ray-induced inhibition of DNA synthesis in human cells: indirect evidence for involvement of calmodulin but not protein kinase C nor p53. Oncogene, 11, 1597-1605.
106. Mirzayans, R., Enns, L., Dietrich, K., Barley, R. D. & Paterson, M. C. (1996). Faulty DNA polymerase δ/ε-mediated excision repair in response to γ radiation or ultraviolet light in p53-deficient fibroblast strains from affected members of a cancer-prone family with Li-Fraumeni syndrome. Carcinogenesis, 17, 691-698.
107. Mirzayans, R., Enns, L. & Paterson, M. C. (1997). Inhibition of DNA synthesis and G1/S transition in normal human fibroblast cultures elicited by a heat-labile trans-acting factor in γ-irradiated HeLa cell extracts. Radiat. Res., 147, 13-21.
108. Mirzayans, R., Scott, A., Cameron, M. & Murray, D. (2005). Induction of accelerated senescence following exposure to ionizing radiation in human solid tumor-derived cell lines expressing wild-type TP53. Radiat. Res., 163, 53-62.
109. Mirzayans, R., Severin, D. & Murray, D. (2006). Relationship between DNA double strand break rejoining and cell survival following exposure to ionizing radiation in human fibroblast strains with differing ATM/p53 function: implications for the evaluation of clinical radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys., 66, 1498-1505.
110. Mirzayans, R., Scott, A., Andrais, B., Pollock, S. & Murray, D. (2008). Ultraviolet light exposure triggers nuclear accumulation of p21WAF1 and accelerated senescence in human normal and nucleotide excision repair-deficient fibroblast strains. J. Cell. Physiol., 215, 55-67.
111. Mirzayans, R., Andrais, B., Scott, A., Paterson, M. C. & Murray, D. (2010). Single-cell analysis of p16INK4a and p21WAF1 expression suggests distinct mechanisms of senescence in normal human and Li-Fraumeni Syndrome fibroblasts. J. Cell. Physiol., 223, 57-67.
112. Morris, M., Hepburn, P. & Wynford-Thomas, D. (2002). Sequential extension of proliferative lifespan in human fibroblasts induced by over-expression of CDK4 or 6 and loss of p53 function. Oncogene, 21, 4277-4288.
113. Munro, J., Steeghs, K., Morrison, V., Ireland, H. & Parkinson, E. K. (2001). Human fibroblast replicative senescence can occur in the absence of extensive cell division and short telomeres. Oncogene, 20, 3541-3552.
114. Murray, D. & Mirzayans, R. (2007). Role of p53 in the repair of ionizing radiation-induced DNA damage. In: Landseer BR Ed. New Research on DNA Repair. Hauppauge, NY, Nova Science Publishers, Inc.; pp. 325-373.
115. Myers, J. S. & Cortez, D. (2006). Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J. Biol. Chem., 281, 9346-9350.
116. Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M. & Smith, J. R. (1994). Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell Res., 211, 90-98.
117. Pang, L. Y., Scott, M., Hayward, R. L., Mohammed, H., Whitelaw, C. B., Smith, G. C. & Hupp, T. R. (2011). p21WAF1 is component of a positive feedback loop that maintains the p53 transcriptional program. Cell cycle, 10, 932-950.
118. Paterson, M. C. & Mirzayans, R. (1993). Correction of post-γ ray DNA repair deficiency in ataxia-telangiectasia complementation group A fibroblasts by cocultivation with normal fibroblasts. In: R. A. Gatti, & R. B. Painter (Eds.), Ataxia-Telangiectasia: NATO ASI series. Berlin, Springer-Verlag. Vol 77, pp. 117-126.
119. Paterson, M. C. & Mirzayans, R. (1999). Methods and compositions for the treatment of ataxia telangiectasia. US Patent Serial No. 5,990,168.
120. Paterson, M. C. & Smith, P. J. (1979). Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Annu. Rev. Genet., 13, 291-318.
121. Paterson, M. C., Smith, B. P., Lohman, P. H. M., Anderson, A. K. & Fishman, L. (1976). Defective excision repair of γ-ray-damaged DNA in human (ataxia telangiectasia) fibroblasts. Nature, 260, 444-447.
122. Pichierri, P., Ammazzalorso, F., Bignami, M. & Franchitto, A. (2011). The Werner syndrome protein: linking the replication checkpoint response to genome stability. Aging (Albany NY), 3, 311-318.
123. Pomerantz, J., Schreiber-Agus, N., Liegeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H. W., Cordon-Cardo. C. & DePinho, R. A. (1998). The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell, 92, 713-723.
124. Orre, L. M., Stenerlow, B., Dhar, S., Larsson, R., Lewensohn, R. & Lehtio, J. (2006). p53 is involved in clearance of ionizing radiation-induced RAD51 foci in a human colon cancer cell line. Biochem. Biophys. Res. Commun., 342, 1211-1217.
125. Rajaraman, R., Guernsey, D. L., Rajaraman, M. M. & Rajaraman, S. R. (2006). Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int., 6, 25.
126. Ramirez, R. D., Morales, C. P., Herbert, B. S., Rohde, J. M., Passons, C., Shay, J. W. & Wright, W. E. (2001). Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev., 15, 398-403.
127. Reliene, R. & Schiestl, R. H. (2008). Experimental antioxidant therapy is ataxia telangiectasia. Clin. Med. Oncol., 2, 431-436.
128. Roninson, I. B. (2003). Tumor cell senescence in cancer treatment. Cancer Res., 63, 2705-2715.
129. Roninson, I. B., Broude, E. V. & Chang, B. D. (2001). If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist. Updates, 4, 303-313.
130. Rotman, G. & Shiloh, Y. (1999). ATM: a mediator of multiple responses to genotoxic stress. Oncogene, 18, 6135-6144.
131. Rousseau, D., Cannella, D., Boulaire, J., Fitzgerald, P., Fotedar, A. & Fotedar, R. (1999) Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway. Oncogene, 18, 4313-4325.
132. Ruaro, E. M., Collavin, L., Sal, G. D., Haffner, R., Oren, M., Levine, A. J. & Schneider, C. (1997). A proline-rich motif in p53 is required for transactivation-independent growth arrest as induced by Gas1. Proc. Natl. Acad. Sci. USA, 94, 4675-4680.
133. Satinover, D. L., Leach, C. A., Stukenberg, P. T. & Brautigan, D. L. (2004). Activation of Aurora-A kinase by protein phosphatase inhibitor-2, a bifunctional signaling protein. Proc. Natl. Acad. Sci. USA, 101, 8625-8630.
134. Sedelnikova, O. A., Horikawa, I., Zimonjic, D. B., Popescu, N. C., Bonner, W. M. & Barrett J. C. (2004). Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol., 6, 168-170.
135. Sengupta, S. & Harris, C. C. (2005). p53: traffic cop at the crossroads of DNA repair and recombination. Nat. Rev. Mol. Cell Biol., 6, 44-55.
136. Shay, J. W. (1999). At the end of the millennium, a view of the end. Nat. Genet., 23, 382-383.
137. Shay, J. W. & Roninson, I. B. (2004). Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene, 23, 2929-2933.
138. Sherr, C. J. & Roberts, J. M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev., 13, 1501-1512.
139. Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer, 3, 155-168.
140. Sliwinska, M. A., Mosieniak, G., Wolanin, K., Babik, A., Piwocka, K., Magalska, A., Szczepanowska, J., Fronk, J. & Sikora, E. (2009). Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells. Mech. Ageing Dev., 130, 24-32.
141. Sohn, D., Essmann, F., Schulze-Osthoff, K. & Jänicke, R. U. (2006). p21 blocks irradiation-induced apoptosis downstream of mitochondria by inhibition of cyclin-dependent kinase-mediated caspase-9 activation. Cancer Res., 66, 11254-11262.
142. Stein, G. H., Drullinger, L. F., Soulard, A. & Dulic, V. (1999). Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell Biol., 19, 2109-2117.
143. Sturzbecher, H. W., Donzelmann, B., Henning, W., Knippschild, U. & Buchhop, S. (1996). p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J., 15, 1992-2002.
144. Suzuki, A., Tsutomi, Y., Yamamoto, N., Shibutani, T. & Akahane, K. (1999). Mitochondrial regulation of cell death: mitochondria are essential for procaspase 3-p21 complex formation to resist Fas-mediated cell death. Mol. Cell. Biol., 19, 3842-3847.
145. Tang, X., Hui, Z. G., Cui, X. L., Garg, R., Kastan, M. B. & Xu. B. (2008). A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage. Mol. Cell. Biol., 28, 2559-2566.
146. Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., Nannmark, U., Samara, C., Pinton, P., Vicencio, J. M., Carnuccio, R., Moll, U. M., Madeo, F., Paterlini-Brechot, P., Rizzuto, R., Szabadkai, G., Pierron, G., Blomgren, K., Tavernarakis, N., Codogno, P., Cecconi, F. & Kroemer, G. (2008). Regulation of autophagy by cytoplasmic p53. Nat. cell Biol., 10, 676-687.
147. Tian, H., Wittmack, E. K. & Jorgensen, T. J. (2000). p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis. Cancer Res., 60, 679-684.
148. Vakifahmetoglu, H., Olsson, M. & Zhivotovsky, B. (2008). Death through a tragedy: mitotic catastrophe. Cell Death Differ., 15, 1153-1162.
149. Warner, S. L., Bearss, D. J., Han, H. & Von Hoff, D. D. (2003). Targeting Aurora-2 kinase in cancer. Mol. Cancer Ther., 2, 589-595.
150. Wei, W., Herbig, U., Wei, S., Dutriaux, A. & Sedivy, J. M. (2003). Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. EMBO Rep., 4, 1061-1066.
151. Wong, K. K., Maser, R. S., Bachoo, R. M., Menon, J., Carrasco, D. R., Gu, Y., Alt, F. W. & DePinho, R. A. (2003). Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature, 421, 643-648.
152. Wood, L. D., Halvorsen, T. L., Dhar, S., Baur, J. A., Pandita, R. K., Wright, W. E., Hande, M. P., Calaf, G., Hei, T. K., Levine, F., Shay, J. W., Wang, J. J. & Pandita, T. K. (2001). Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene, 20, 278-288.
153. Wouters, B. G., Giaccia, A. J., Denko, N. C. & Brown, J. M. (1997). Loss of p21Waf1/Cip1 sensitizes tumors to radiation by an apoptosis-independent mechanism. Cancer Res., 57, 4703-4706.
154. Xiong, Y., Hannon, G. J., Zhang, H., Casso, D., Kobayashi, R. & Beach, D. (1993a). p21 is a universal inhibitor of cyclin kinases. Nature, 366, 701-704.
155. Xiong, Y., Zhang, H. & Beach, D. (1993b). Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev., 7, 1572-1583.
156. Xu, H. J., Zhou, Y., Ji, W., Perng, G. S., Kruzelock, R., Kong, C. T., Bast, R. C., Mills, G. B., Li, J. & Hu, S. X. (1997). Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene, 15, 2589-2596.
157. Yang, W. L., Zeng, Y. X., El Deiry, W. S., Nason-Burchenal, K., Dmitrovsky, E. & Chin, K. V. (1999). Transcriptional activation of the cyclin-dependent kinase inhibitor p21 by PML/RARalpha. Mol. Cell Biol. Res. Commun., 1, 125-131.
158. Zgheib, O., Huyen, Y., DiTullio, R. A. Jr., Snyder, A., Venere, M., Stavridi, E. S. & Halazonetis, T. D. (2005). ATM signaling and 53BP1. Radiother. Oncol., 76, 119-122.
159. Zhang, H. (2007). Molecular signaling and genetic pathways of senescence: its role in tumorigenesis and aging. J. Cell Physiol., 210, 567-574.
160. Zhang, Y., Xiong, Y. & Yarbrough, W. G. (1998). ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell, 92, 725-734.
161. Zhang, X. P., Liu, F. & Wang, W. (2011). Two-phase dynamics of p53 in the DNA damage response. Proc. Natl. Acad. Sci. USA, 108, 8990-8995.
162. Zhou, B. P. & Hung, M. C. (2002). Novel targets of Akt, p21Cip1/WAF1, and MDM2. Semin. Oncol. 29, 2-70.