Chapter 23 : DNA Damage and the Regulation of Cell Fate

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in

DNA Damage and the Regulation of Cell Fate, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816704/9781555813192_Chap23-1.gif /docserver/preview/fulltext/10.1128/9781555816704/9781555813192_Chap23-2.gif


This chapter discusses decisions about long-term cell fate that is intimately connected with regulatory responses to DNA-damaging agents in eukaryotes. The cell may attempt cell cycle progression while damage persists, a process termed adaptation. The chapter first describes the adaptation process and cell cycle restart. Adaptation in budding yeast correlates with active silencing of downstream effector kinases. Then, it introduces extrinsic and intrinsic pathways of apoptosis. The impact of other DNA damage-responsive transcriptional pathways that counteract or cooperate with p53 on apoptosis is also considered. Next, it briefly examines the relationships between DNA damage and senescence. Certain critical players determining cell fate during senescence that are overlapping with DNA damage responses have been described. Differentiation is an insufficiently understood response to DNA damage and is most probably triggered by slowed replication. In , the filamentous differentiation induced under such conditions is dependent on a subset of the DNA damage/replication checkpoint proteins (Rad53 and Mec1). However, in mammalian cells a checkpoint-like reversible inhibition of differentiation has also been shown after treatment with various DNA-damaging agents. All of these responses are important in the context of cancer and especially cancer therapy, where DNA-damaging agents are routinely employed to attain preferential killing of cancer cells. The chapter addresses selected aspects of these phenomena in the DNA damage context.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23

Key Concept Ranking

Tumor Necrosis Factor Receptor Family
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 23–1
Figure 23–1

Assessment systems for DNA damage in and its influence on the threshold for adaptation. Presence of the yeast Ku complex (Yku70, Yku80) at a DSB site diminishes the damage signal and enables adaptation. The likely reason is the reduced DNA degradation around the DSB and, as a consequence, reduced binding of RPA (consisting of Rfa1, Rfa2, and Rfa3) signaling the presence of single-stranded DNA. The binding of the RecA homolog Rad51 or of Srs2 helicase dampens the damage signal (and, consequently, mutants fail to adapt). The interaction of Rad51 with Rad52 is essential for this effect. The presence of Rad52 without Rad51 has the opposite effect, enhancing the damage signal and increasing the adaptation threshold.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–2
Figure 23–2

Genetic consequences of adaptation to ionizing radiation damage in (Top) Cells of a DSB repair-deficient but adaptation-competent diploid strain (left) and an adaptation-deficient derivative (right) were plated (100,000 versus 30,000 per plate) and treated with 30 Gy of γ-irradiation. As the result of adaptation, small, slow-growing colonies with chromosome aberrations arise in the adaptation-competent strain. (Bottom) Disomic haploid strains show enhanced spontaneous chromosome loss as a result of adaptation to spontaneous DSB. An extra copy of chromosome VII carries wild-type complementing an defect in an otherwise mutant cell. Loss of the additional chromosome results in loss of red pigmentation (loss is indicated by white sectors in grey area) (see Fig. 17–3). This is evident for the wild type (left) but much less so for the adaptation-deficient strain (right). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–3
Figure 23–3

Some landmarks of apoptosis. Activation of an apoptotic pathway results in rounding of an adherent cell, DNA condensation, and fragmentation. Finally, disintegration of the entire cell into membrane-bound vesicles (apoptotic bodies) occurs. These can be phagocytosed by macrophages. The schematized agarose gel demonstrates the appearance of a ladder of DNA fragments during progressing apoptosis, indicating nuclease attack in internucleosomal regions of chromatin. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–4
Figure 23–4

Pathways of apoptosis. (A) In this scheme for extrinsic triggering of apoptosis, FAS ligand-mediated multimer formation of the FAS receptor and downstream activation of caspase-8 by autocleavage is depicted. (B) Intrinsic activation of apoptosis involves the BCL-2 family members that effect cytochrome release from mitochondria. Binding of cytochrome to the adaptor protein APAF-1 leads to the assembly of the apoptosome and caspase-9 activation. Consequently, downstream-acting caspases are also activated. Release of additional mitochondrial factors (SMAC/DIABLO) counteracts the inhibitors of those caspases (inhibitors of apoptotic proteins [IAP]). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–5
Figure 23–5

Scheme of the various transcriptional and nontranscriptional roles of p53 contributing to apoptosis. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–6
Figure 23–6

Domain structure of p63, p73, p53, and its various alternative splicing products. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–7
Figure 23–7

H1 histone distribution following IR treatment. (A) Histone H1 species are detected by Western blotting in the cytoplasmic extract fraction shown. An increased amount correlates with the fraction of apoptotic cells following IR exposure. (B) Detection of cytoplasmic dispersal of H1 histone following IR treatment by immunocytochemistry. NT, not treated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–8
Figure 23–8

The response of human fibroblasts to senescence associated with telomere shortening is reminiscent of a DNA damage response (20 Gy of IR given to proliferating cells). Accumulation of 7H2AX and phosphorylated SMC1, RAD17, CHK1, and CHK2 proteins is measured using phosphospecific and phosphononspecific antibodies, as indicated to the right. The relevant protein bands are marked by asterisks if needed. For comparison, results with a comparable cell line forcibly expressing telomerase that had been grown for more generations than the senescent line are also shown (labeled “Proliferating telomerized”). Note that RAD17 also undergoes phosphorylation of Ser654 in S phase but in nondividing cells this phosphorylation is specific for senescent cells. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–9
Figure 23–9

Scheme for aging responses resulting in genetic instability triggered by telomere shortening. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 23–10
Figure 23–10

DNA damage-induced checkpoint arrest can protect from lethal effects of a drug whose effect is confined to mitosis. Wild-type cells and those deficient in p21 regulation were treated with the DNA-damaging agent doxorubicin. This drug causes mostly G arrest in HCT116 cells harboring wild-type p53 and thus having normal induction. Doxorubicin treatment protects from the lethal consequence of the microtubule drug paclitaxel (PTX, measured as loss in optical density of the culture [OD]) only if DNA damage checkpoint arrest is not compromised. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Acehan, D.,, X. Jiang,, D. G. Morgan,, J. E. Heuser,, X. Wang, and, C. W. Akey. 2002. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell 9:423432.
2. Adams, J., 2003. Ways of dying: multiple pathways of apoptosis. Genes Dev. 17:24812495.
3. Adrain, C.,, E. M. Creagh, and, S. J. Martin. 2001. Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO J. 20:66276636.
4. Agami, R.,, G. Blandino,, M. Oren, and, Y. Shaul. 1999. Interaction of c-Abl and p73α and their collaboration to induce apoptosis. Nature 399:809813.
5. Ahmed, S., and, J. Hodgkin. 2000. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403:159164.
6. Alvarez-Gonzalez, R.,, H. Spring,, M. Müller, and, A. Bürkle. 1999. Selective loss of poly(ADP-ribose) and the 85-kDa fragment of poly(ADP-ribose) polymerase in nucleoli during alkylation-induced apoptosis of HeLa cells. J. Biol. Chem. 274:3212232126.
7. An, W.,, J. Kim, and, G. S. Roeder. 2004. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117:735748.
8. Ashkenazi, A., 2002. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2:420430.
9. Attardi, L. D.,, E. E. Reczek,, C. Cosmas,, E. G. Demicco,, M. E. Mc-Currach,, S. W. Lowe, and, T. Jacks. 2000. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 14:704718.
10. Bakkenist, C. J., and, M. B. Kastan. 2004. Phosphatases join kinases in DNA-damage response pathways. Trends Cell Biol. 14:339341.
11. Bennett, C. B.,, T. J. Westmoreland,, J. R. Snipe, and, M. A. Resnick. 1996. A double-strand break within a yeast artificial chromosome (YAC) containing human DNA can result in YAC loss, deletion, or cell lethality. Mol. Cell. Biol. 16:44144425.
12. Bergamaschi, D.,, Y. Samuels,, N. J. O’Neil,, G. Trigiante,, T. Crook,, J. K. Hsieh,, D. J. O’Connor,, S. Zhong,, I. Campargue,, M. L. Tomlinson,, P. E. Kuwabara, and, X. Lu. 2003. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 33:162167.
13. Bergeron, L.,, G. I. Perez,, G. Macdonald,, L. Shi,, Y. Sun,, A. Ju-risicova,, S. Varmuza,, K. E. Latham,, J. A. Flaws,, J. C. Salter,, H. Hara,, M. A. Moskowitz,, E. Li,, A. Greenberg,, J. L. Tilly, and, J. Yuan. 1998. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev. 12:13041314.
14. Bernardi, R.,, P. Scaglioni,, S. Bergmann,, H. Horn,, K. H. Vousden, and, P. P. Pandolfi. 2004. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat. Cell Biol. 6:665672.
15. Bissonnette, N., and, D. J. Hunting. 1998. p21-induced cell cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16:34613469.
16. Blackburn, E. H., 2000. Telomere states and cell fates. Nature 408:5356.
17. Blagosklonny, M. V., and, A. B. Pardee. 2001. Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res. 61:43014305.
18. Blagosklonny, M. V.,, R. Robey,, S. Bates, and, T. Fojo., 2000. Pre-treatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs. J. Clin. Investig. 105:533–539.
19. Boatright, K. M.,, M. Renatus,, F. L. Scott,, S. Sperandio,, H. Shin,, I. M. Pedersen,, J. E. Ricci,, W. A. Edris,, D. P. Sutherlin,, D. R. Green, and, G. S. Salvesen. 2003. A unified model for apical caspase activation. Mol. Cell 11:529541.
20. Brachman, D. G.,, M. Beckett,, D. Graves,, D. Haraf,, E. Vokes, and, R. R. Weichselbaum. 1993. p53 mutation does not correlate with ra-diosensitivity in 24 head and neck cancer cell lines. Cancer Res. 53:36673669.
21. Bree, R.,, C. Neary,, A. Samali, and, N. F. Lowndes. 2004. The switch from survival responses to apoptosis after chromosomal breaks. DNA Repair 3:989995.
22. Brodsky, M. H.,, W. Nordstrom,, G. Tsang,, E. Kwan,, G. M. Rubin, and, J. M. Abrams. 2000. Drosophila p53 binds a damage response element at the reaper locus. Cell 101:103113.
23. Bulavin, D. V.,, S. Saito,, M. C. Hollander,, K. Sakaguchi,, C. W. Anderson,, E. Appella, and, A. J. Fornace, Jr., 1999. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 18:68456854.
24. Busby, E. C.,, D. F. Leistritz,, R. T. Abraham,, L. M. Karnitz, and, J. N. Sarkaria. 2000. The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res. 60:21082112.
25. Caelles, C.,, A. Helmberg, and, M. Karin. 1994. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370:220223.
26. Campisi, J., 2003. Cancer and ageing: rival demons? Nat. Rev. Cancer 3:339349.
27. Carbone, R.,, M. Pearson,, S. Minucci, and, P. G. Pelicci. 2002. PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage. Oncogene 21:16331640.
28. Castedo, M.,, J. L. Perfettini,, T. Roumier,, K. Andreau,, R. Medema, and, G. Kroemer. 2004. Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:28252837.
29. Chao, C.,, S. Saito,, J. Kang,, C. W. Anderson,, E. Appella, and, Y. Xu. 2000. p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage. EMBO J. 19:49674975.
30. Chen, X.,, Y. Zheng,, J. Zhu,, J. Jiang, and, J. Wang. 2001. p73 is transcriptionally regulated by DNA damage, p53 and p73. Oncogene 20:769774.
31. Cheung, W. L.,, K. Ajiro,, K. Samejima,, M. Kloc,, P. Cheung,, C. A. Mizzen,, A. Beeser,, L. D. Etkin,, J. Chernoff,, W. C. Earnshaw, and, C. D. Allis. 2003. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113:507517.
32. Chiou, S. K.,, L. Rao, and, E. White. 1994. Bcl-2 blocks p53-dependent apoptosis. Mol. Cell. Biol. 14:25562563.
33. Chipuk, J. E.,, T. Kuwana,, L. Bouchier-Hayes,, N. M. Droin,, D. D. Newmeyer,, M. Schuler, and, D. R. Green. 2004. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apopto-sis. Science 303:10101014.
34. Cooper, G., and, R. Hausman. 2004. The Cell: a Molecular Approach. ASM Press/Sinauer Associates, Washington, D.C., and Sunderland, Mass.
35. Costanzo, A.,, P. Merlo,, N. Pediconi,, M. Fulco,, V. Sartorelli,, P. A. Cole,, G. Fontemaggi,, M. Fanciulli,, L. Schiltz,, G. Blandino,, C. Balsano, and, M. Levrero. 2002. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol. Cell 9:175186.
36. Coultas, L., and, A. Strasser., 2000. The molecular control of DNA damage-induced cell death. Apoptosis 5:491507.
37. Cuddihy, A. R., and, R. G. Bristow. 2004. The p53 protein family and radiation sensitivity: yes or no? Cancer Metast. Rev. 23:237257.
38. Curtis, H., 2004. Biological mechanisms underlying the aging process. Science 141:686694.
39. Cutler, R. G., 1984. Antioxidants, aging, and longevity, p.,371428. In W. A. Pryor, (ed.)., Free Radicals in Biology. Academic Press, Inc., New York, N.Y.
40. d’Adda di Fagagna, F.,, P. M. Reaper,, L. Clay-Farrace,, H. Fiegler,, P. Carr,, T. von Zglinicki,, G. Saretzki,, N. P. Carter, and, S. P. Jackson. 2003. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194198.
41. de Lange, T., 2002. Protection of mammalian telomeres. Oncogene 21:532540.
42. Dellaire, G., and, D. Bazett-Jones. 2004. PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26:963977.
43. den Elzen, N., and, M. O’Connell. 2004. Recovery from DNA damage checkpoint arrest by PP1-mediated inhibition of Chk1. EMBO J. 23:908918.
44. Derry, W. B.,, A. P. Putzke, and, J. H. Rothman. 2001. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294:591595.
45. Deveraux, Q. L.,, R. Takahashi,, G. S. Salvesen, and, J. C. Reed. 1997. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300304.
46. Di Leonardo, A.,, S. P. Linke,, K. Clarkin, and, G. M. Wahl. 1994. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8:25402551.
47. Dodson, H.,, E. Bourke,, L. J. Jeffers,, P. Vagnarelli,, E. Sonoda,, S. Takeda,, W. C. Earnshaw,, A. Merdes, and, C. Morrison. 2004. Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM. EMBO J. 23:38643873.
48. Donehower, L. A.,, M. Harvey,, B. L. Slagle,, M. J. McArthur,, C. A. Montgomery, Jr.,, J. S. Butel, and, A. Bradley. 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215221.
49. Duchaud, E.,, A. Ridet,, D. Stoppa-Lyonnet,, N. Janin,, E. Mous-tacchi, and, F. Rosselli. 1996. Deregulated apoptosis in ataxia telangiecta-sia: association with clinical stigmata and radiosensitivity. Cancer Res. 56:14001404.
50. Ellisen, L. W.,, K. T. Ramsayer,, C. M. Johannesen,, A. Yang,, B. H., K. Minda,, J. D. Oliner,, F. McKeon, and, D. A. Haber. 2002. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol. Cell 10:9951005.
51. Enari, M.,, H. Sakahira,, H. Yokoyama,, K. Okawa,, A. Iwamatsu, and, S. Nagata. 1998. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:4350.
52. Erster, S.,, M. Mihara,, R. H. Kim,, O. Petrenko, and, U. M. Moll. 2004. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol. Cell. Biol. 24:67286741.
53. Esashi, F., and, M. Yanagida. 1999. Cdc2 phosphorylation of Crb2 is required for reestablishing cell cycle progression after the damage checkpoint. Mol. Cell 4:167174.
54. Fan, S.,, M. L. Smith,, D. J. Rivet II,, D. Duba,, Q. Zhan,, K. W. Kohn,, A. J. Fornace, Jr., and, P. M. O’Connor. 1995. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res. 55:16491654.
55. Fei, P., and, W. S. El-Deiry. 2003. P53 and radiation responses. Onco-gene 22:57745783.
56. Fernández-Salas, E.,, K. S. Suh,, V. V. Speransky,, W. L. Bowers,, J. M. Levy,, T. Adams,, K. R. Pathak,, L. E. Edwards,, D. D. Hayes,, C. Cheng,, A. C. Steven,, W. C. Weinberg, and, S. H. Yuspa. 2002. mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53. Mol. Cell. Biol. 22:36103620.
57. Flores, E. R.,, K. Y. Tsai,, D. Crowley,, S. Sengupta,, A. Yang,, F. McKeon, and, T. Jacks. 2002. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560564.
58. Ford, J. M., and, P. C. Hanawalt. 1995. Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc. Natl. Acad. Sci. USA 92:88768880.
59. Fridman, J. S., and, S. W. Lowe. 2003. Control of apoptosis by p53. Oncogene 22:90309040.
60. Friedlander, P.,, Y. Haupt,, C. Prives, and, M. Oren. 1996. A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol. Cell. Biol. 16:49614971.
61. Friesen, C.,, I. Herr,, P. H. Krammer, and, K. M. Debatin. 1996. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat. Med. 2:574577.
62. Galgoczy, D. J., and, D. P. Toczyski. 2001. Checkpoint adaptation precedes spontaneous and damage-induced genomic instability in yeast. Mol. Cell. Biol. 21:17101718.
63. Garcia-Cao, I.,, M. Garcia-Cao,, J. Martin-Caballero,, L. M. Criado,, P. Klatt,, J. M. Flores,, J. C. Weill,, M. A. Blasco, and, M. Serrano. 2002. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21:62256235.
64. Gartner, A.,, S. Milstein,, S. Ahmed,, J. Hodgkin, and, M. O. Hen-gartner. 2000. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell 5:435443.
65. Giordano, A., and, K. J. Soprano (ed.)., 2003. Cell Cycle Inhibitors in Cancer Therapy: Current Strategies. Humana Press, Totowa, N.J.
66. Gong, J.,, A. Costanzo,, H.-Q. Yang,, G. Melino,, W. G. Kaelin, Jr.,, M. Levrero, and, J. Y. J. Wang. 1999. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399:806809.
67. Gonzalez, S.,, C. Prives, and, C. Cordon-Cardo. 2003. p73a regulation by Chk1 in response to DNA damage. Mol. Cell. Biol. 23:81618171.
68. Griffin, J.,, D. Munroe,, P. Major, and, D. Kufe. 1982. Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis. Exp. Hematol. 10:774781.
69. Gross, A.,, J. M. McDonnell, and, S. J. Korsmeyer. 1999. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:18991911.
70. Guan, J.,, S. DiBiase, and, G. Iliakis. 2000. The catalytic subunit DNA-dependent protein kinase (DNA-PKcs) facilitates recovery from radiation-induced inhibition of DNA replication. Nucleic Acids Res. 28:11831192.
71. Hackett, J. A., and, C. W. Greider. 2003. End resection initiates genomic instability in the absence of telomerase. Mol. Cell. Biol. 23:84508461.
72. Haimovitz-Friedman, A.,, R. Kolesnick, and, Z. Fuks. 1996. Modulation of the apoptotic response: potential for improving the outcome in clinical radiotherapy. Semin. Radiat. Oncol. 6:273283.
73. Hakem, R.,, A. Hakem,, G. S. Duncan,, J. T. Henderson,, M. Woo,, M. S. Soengas,, A. Elia,, J. L. de la Pompa,, D. Kagi,, W. Khoo,, J. Potter,, R. Yoshida,, S. A. Kaufman,, S. W. Lowe,, J. M. Penninger, and, T. W. Mak. 1998. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339352.
74. Haldar, S.,, M. Negrini,, M. Monne,, S. Sabbioni, and, C. M. Croce. 1994. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 54:20952097.
75. Hall, E., 2000. Radiobiology for the Radiologist, 5th ed. Lippincott Williams & Wilkins, Philadelphia, Pa.
76. Heise, C.,, A. Sampson-Johannes,, A. Williams,, F. McCormick,, D. D. Von Hoff, and, D. H. Kirn. 1997. ONYX-015, anE1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat. Med. 3:606608.
77. Herbig, U.,, W. A. Jobling,, B. P. Chen,, D. J. Chen, and, J. M. Se-divy. 2004. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14:501513.
78. Herold, S.,, M. Wanzel,, V. Beuger,, C. Frohme,, D. Beul,, T. Hillukkala,, J. Syvaoja,, H.-P. Saluz,, F. Haenel, and, M. Eilers. 2002. Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol. Cell 10:509521.
79. Hodges, M.,, C. Tissot,, K. Howe,, D. Grimwade, and, P. S. Freemont. 1998. Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies. Am. J. Hum. Genet. 63:297304.
80. Hoffman, W. H.,, S. Biade,, J. T. Zilfou,, J. Chen, and, M. Murphy. 2002. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277:32473257.
81. Huang, D. C., and, A. Strasser. 2000. BH3-only proteins—essential initiators of apoptotic cell death. Cell 103:839842.
82. Hwang, P. M.,, F. Bunz,, J. Yu,, C. Rago,, T. A. Chan,, M. P. Murphy,, G. F. Kelso,, R. A. Smith,, K. W. Kinzler, and, B. Vogelstein. 2001. Ferre-doxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat. Med. 7:11111117.
83. Igney, F. H., and, P. H. Krammer. 2002. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2:277288.
84. Ihrie, R. A.,, E. Reczek,, J. S. Horner,, L. Khachatrian,, J. Sage,, T. Jacks, and, L. D. Attardi. 2003. Perp is a mediator of p53-dependent apoptosis in diverse cell types. Curr. Biol. 13:19851990.
85. IJpma, A., and, C. W. Greider. 2003. Short telomeres induce a DNA damage response inSaccharomyces cerevisiae. Mol. Biol. Cell 14:9871001.
86. Ishizaki, K.,, Y. Ejima,, T. Matsunaga,, R. Hara,, A. Sakamoto,, M. Ikenaga,, Y. Ikawa, and, S. Aizawa. 1994. Increased UV-induced SCEs but normal repair of DNA damage in p53-deficient mouse cells. Int. J. Cancer 58:254257.
87. Israeli, D.,, E. Tessler,, Y. Haupt,, A. Elkeles,, S. Wilder,, R. Amson,, A. Telerman, and, M. Oren. 1997. A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J. 16:43844392.
88. Jacks, T.,, L. Remington,, B. O. Williams,, E. M. Schmitt,, S. Ha-lachmi,, R. T. Bronson, and, R. A. Weinberg. 1994. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4:17.
89. Jiang, X., and, X. Wang. 2004. Cytochrome C-mediated apoptosis. Annu. Rev. Biochem. 73:87106.
90. Jiang, Y. W., and, C. M. Kang. 2003. Induction of S. cerevisiae filamentous differentiation by slowed DNA synthesis involves Mec1, Rad53 and Swe1 checkpoint proteins. Mol. Biol. Cell 14:51165124.
91. Jimenez, G. S.,, M. Nister,, J. M. Stommel,, M. Beeche,, E. A. Bar-case,, X.-Q. Zhang,, S. O’Gorman, and, G. M. Wahl. 2000. A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat. Genet. 26:3743.
92. Johnson, T. M.,, Z.-X. Yu,, V. J. Ferrans,, R. A. Lowenstein, and, T. Finkel. 1996. Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl. Acad. Sci. USA 93:1184811852.
93. Kaeser, M. D., and, R. D. Iggo. 2002. Chromatin immunoprecip-itation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl. Acad. Sci. USA 99:95100.
94. Kaghad, M.,, H. Bonnet,, A. Yang,, L. Creancier,, J.-C. Biscan,, A. Va-lent,, A. Minty,, P. Chalon,, J.-M. Lelias,, X. Dumont,, P. Ferrara,, F. McKeon, and, D. Caput. 1997. Monoallelic expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809819.
95. Karin, M., and, A. Lin. 2002. NF-κB at the crossroads of life and death. Nat. Immunol. 3:221227.
96. Karlseder, J.,, K. Hoke,, O. K. Mirzoeva,, C. Bakkenist,, M. B. Kastan,, J. H. J. Petrini, and, T. de Lange. 2004. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol. 2:11501156.
97. Karlseder, J.,, A. Smogorzewska, and, T. de Lange. 2002. Senescence induced by altered telomere state, not telomere loss. Science 295:24462449.
98. Kasibhatla, S.,, T. Brunner,, L. Genestier,, F. Echeverri,, A. Mah-boubi, and, D. R. Green. 1998. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1. Mol. Cell 1:543551.
99. Katoh, I.,, K. Aisaki,, S. Kurata,, S. Ikawa, and, Y. Ikawa. 2000. p51A (TAp63γ-), a p53 homolog, accumulates in response to DNA damage for cell regulation. Oncogene 19:31263130.
100. Kawai, H.,, Y. Yamada,, M. Tatsuka,, O. Niwa,, K. Yamamoto, and, F. Suzuki. 1999. Down-regulation of nuclear factor κB is required for p53-dependent apoptosis in X-ray-irradiated mouse lymphoma cells and thymocytes. Cancer Res. 59:60386041.
101. Keramaris, E.,, A. Hirao,, R. S. Slack,, T. W. Mak, and, D. S. Park. 2003. Ataxia telangiectasia-mutated protein can regulate p53 and neuronal death independent of Chk2 in response to DNA damage. J. Biol. Chem. 278:3778237789.
102. Kinzler, K. W., and, B. Vogelstein. 1998. Landscaping the cancer terrain. Science 280:10361037.
103. Ko, L. J., and, C. Prives. 1996. p53: puzzle and paradigm. Genes Dev. 10:10541072.
104. Komatsu, K.,, T. Miyashita,, H. Hang,, K. M. Hopkins,, W. Zheng,, S. Cuddeback,, M. Yamada,, H. B. Lieberman, and, H. G. Wang. 2000. Human homologue of S. pombeRad9 interacts with BCL-2/BCL-xL and promotes apoptosis. Nat. Cell Biol. 2:16.
105. Koniaras, K.,, A. R. Cuddihy,, H. Christopoulos,, A. Hogg, and, M. J. O’Connell. 2001. Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene 20:74537463.
106. Konishi, A.,, S. Shimizu,, J. Hirota,, T. Takao,, Y. Fan,, Y. Matsuoka,, L. Zhang,, Y. Yoneda,, Y. Fujii,, A. I. Skoultchi, and, Y. Tsujimoto. 2003. Involvement of histone H1.2 in apoptosis induced by DNA double-strand breaks. Cell 114:673688.
107. Kuida, K.,, T. F. Haydar,, C. Y. Kuan,, Y. Gu,, C. Taya,, H. Kara-suyama,, M. S. Su,, P. Rakic, and, R. A. Flavell. 1998. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325337.
108. Kulms, D.,, E. Zeise,, B. Poppelmann, and, T. Schwarz. 2002. DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way. Oncogene 21:58445851.
109. Lane, D. P., 1992. p53, guardian of the genome. Nature 358:1516.
110. Lassus, P.,, M. Ferlin,, J. Piette, and, U. Hibner. 1996. Anti-apoptotic activity of low levels of wild-type p53. EMBO J. 15:45664573.
111. Lassus, P.,, X. Opitz-Araya, and, Y. Lazebnik. 2002. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabi-lization. Science 297:13521354.
112. Latella, L.,, J. Lukas,, C. Simone,, P. L. Puri, and, J. Bartek. 2004. Differentiation-induced radioresistance in muscle cells. Mol. Cell. Biol. 24: 63506361.
113. Lau, C. C., and, A. B. Pardee. 1982. Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc. Natl. Acad. Sci. USA 79:29422946.
114. Lazebnik, Y. A.,, S. H. Kaufmann,, S. Desnoyers,, G. G. Poirier, and, W. C. Earnshaw. 1994. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346347.
115. Lee, E.,, A. Nakatsuma,, R. Hiraoka,, E. Ishikawa,, R. Enomoto, and, A. Yamauchi. 1999. Involvement of histone phosphorylation in thy-mocyte apoptosis by protein phosphatase inhibitors. IUBMB Life 48:7983.
116. Lee, J. M., and, A. Bernstein. 1993. p53 mutations increase resistance to ionizing radiation. Proc. Natl. Acad. Sci. USA 90:57425756.
117. Lee, S. E.,, J. K. Moore,, A. Holmes,, K. Umezu,, R. D. Kolodner, and, J. E. Haber. 1998. Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94:399409.
118. Lee, S. E.,, A. Pellicioli,, A. Malkova,, M. Foiani, and, J. E. Haber. 2001. The Saccharomyces recombination protein Tid1p is required for adaptation from G2/M arrest induced by a double-strand break. Curr. Biol. 11:10531057.
119. Lee, S. E.,, A. Pellicioli,, M. B. Vaze,, N. Sugawara,, A. Malkova,, M. Foiani, and, J. E. Haber. 2003. Yeast Rad52 and Rad51 recombination proteins define a second pathway of DNA damage assessment in response to a single double-strand break. Mol. Cell. Biol. 23:89138923.
120. Lee, Y., and, P. J. McKinnon. 2000. ATM dependent apoptosis in the nervous system. Apoptosis 5:523529.
121. Lengauer, C.,, K. W. Kinzler, and, B. Vogelstein. 1998. Genetic instabilities in human cancers. Nature 396:643649.
122. Leroy, C.,, S. E. Lee,, M. B. Vaze,, F. Ochsenbien,, R. Guerois,, J. E. Haber, and, M. C. Marsolier-Kergoat. 2003. PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. Mol. Cell 11:827835.
123. Leu, J. I.,, P. Dumont,, M. Hafey,, M. E. Murphy, and, D. L. George. 2004. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol. 6:443450.
124. Li, L. Y.,, X. Luo, and, X. Wang. 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:9599.
125. Li, P.,, D. Nijhawan,, I. Budihardjo,, S. M. Srinivasula,, M. Ahmad,, E. S. Alnemri, and, X. Wang. 1997. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479489.
126. Li, P. F.,, R. Dietz, and, R. von Harsdorf. 1999. p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J. 18:60276036.
127. Lin, W.-C.,, F.-T. Lin, and, J. R. Nevins. 2001. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev. 15:18331844.
128. Linke, S. P.,, K. C. Clarkin, and, G. M. Wahl. 1997. p53 mediates permanent arrest over multiple cell cycles in response to γ-irradiation. Cancer Res. 57:11711179.
129. Loeb, L. A., 2001. A mutator phenotype in cancer. Cancer Res. 61:32303239.
130. Loeb, L. A.,, K. R. Loeb, and, J. P. Anderson. 2003. Multiple mutations and cancer. Proc. Natl. Acad. Sci. USA 100:776781.
131. Lowe, S. W., 1995. Cancer therapy and p53. Curr. Opin. Oncol. 7:547553.
132. Luo, X.,, I. Budihardjo,, H. Zou,, C. Slaughter, and, X. Wang. 1998. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481490.
133. Luo, Y.,, S. K. Rockow-Magnone,, M. K. Joseph,, J. Bradner,, C. C. Butler,, S. K. Tahir,, E. K.- H. Han,, S.-C. Ng,, J. M. Severin,, E. J. Gubbins,, R. M. Reilly,, A. Rueter,, R. L. Simmer,, T. F. Holzman, and, V. L. Giranda. 2001. Abrogation of G2 checkpoint specifically sensitize p53 defective cells to cancer chemotherapeutic agents. Anticancer Res. 21:2328.
134. Macip, S.,, M. Igarashi,, P. Berggren,, J. Yu,, S. W. Lee, and, S. A. Aaronson. 2003. Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. 23:85768585.
135. Marchenko, N. D.,, A. Zaika, and, U. M. Moll. 2000. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem. 275:1620216212.
136. Martin, G.,, S. Austad, and, T. Johnson. 1996. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat. Genet. 13: 2534.
137. Martin, S. J.,, D. R. Green, and, T. G. Cotter. 1994. Dicing with death: dissecting the components of the apoptosis machinery. Trends Biochem. Sci. 19:2630.
138. Maser, R. S., and, R. A. DePinho. 2002. Connecting chromosomes, crisis, and cancer. Science 297:565569.
139. McIlwrath, A. J.,, P. A. Vasey,, G. M. Ross, and, R. Brown. 1994. Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity. Cancer Res. 54:37183722.
140. Michaelson, J. S.,, D. Bader,, F. Kuo,, C. Kozak, and, P. Leder. 1999. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13:19181923.
141. Michaelson, J. S., and, P. Leder. 2003. RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX. J. Cell Sci. 116:345352.
142. Migliaccio, E.,, M. Giorgio,, S. Mele,, G. Pelicci,, P. Reboldi,, P. P.xs Pandolfi,, L. Lanfrancone, and, P. G. Pelicci. 1999. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309313.
143. Mihara, M.,, S. Erster,, A. Zaika,, O. Petrenko,, T. Chittenden,, P. Pancoska, and, U. M. Moll. 2003. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11:577590.
144. Miyake, H.,, N. Hanada,, H. Nakamura,, S. Kagawa,, T. Fujiwara,, I. Hara,, H. Eto,, K. Gohji,, S. Arakawa,, S. Kamidono, and, H. Saya. 1998. Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer. Oncogene 16:933943.
145. Miyashita, T.,, S. Krajewski,, M. Krajewska,, H. G. Wang,, H. K. Lin,, D. A. Liebermann,, B. Hoffman, and, J. C. Reed. 1994. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9:17991805.
146. Miyashita, T., and, J. C. Reed. 1995. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293299.
147. Müller, M.,, S. Wilder,, D. Bannasch,, D. Israeli,, K. Lehlbach,, M. Li-Weber,, S. L. Friedman,, P. R. Galle,, W. Stremmel,, M. Oren, and, P. H. Krammer. 1998. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188:20332045.
148. Munoz, P.,, F. Baus, and, J. Piette. 2001. Ku antigen is required to relieve G2 arrest caused by inhibition of DNA toposiomerase II activity by the bisdioxopiperazine ICRF-193. Oncogene 20:19901999.
149. Nakano, K., and, K. H. Vousden. 2001. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7:683694.
150. Nitta, M.,, O. Kobayashi,, S. Honda,, T. Hirota,, S. Kuninaka,, T. Marumoto,, Y. Ushio, and, H. Saya. 2004. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene 23:65486558.
151. Norbury, C. J., and, B. Zhivotovsky. 2004. DNA damage-induced apoptosis. Oncogene 23:27972808.
152. Ollmann, M.,, L. M. Young,, C. J. Di Como,, F. Karim,, M. Belvin,, S. Robertson,, K. Whittaker,, M. Demsky,, W. W. Fisher,, A. Buchman,, G. Duyk,, L. Friedman,, C. Prives, and, C. Kopczynski. 2000. Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101:91101.
153. Oltvai, Z. N., and, S. J. Korsmeyer. 1994. Checkpoints of dueling dimers foil death wishes. Cell 79:189192.
154. Orr, W. C., and, R. S. Sohal. 1994. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263:11281130.
155. Paulovich, A. G.,, D. P. Toczyski, and, L. H. Hartwell. 1997. When checkpoints fail. Cell 88:315321.
156. Pearson, M.,, R. Carbone,, C. Sebastiani,, M. Cioce,, M. Fagioli,, S. Saito,, Y. Higashimoto,, E. Appella,, S. Minucci,, P. P. Pandolfi, and, P. G. Pelicci. 2000. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406:207210.
157. Pellicioli, A.,, S. E. Lee,, C. Lucca,, M. Foiani, and, J. E. Haber. 2001. Regulation of Saccharomyces Rad53 checkpoint kinase during adaptation from DNA damage-induced G2/M arrest. Mol. Cell 7:293300.
158. Polyak, K.,, Y. Xia,, J. L. Zweier,, K. W. Kinzler, and, B. Vogelstein. 1997. A model for p53-induced apoptosis. Nature 389:300305.
159. Powell, S. N.,, J. S. DeFrank,, P. Connell,, M. Eogan,, F. Preffer,, D. Dombkowski,, W. Tang, and, S. Friend. 1995. Differential sensitivity of p53(_) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res. 55:16431648.
160. Puri, P. L.,, K. Bhakta,, L. D. Wood,, A. Costanzo,, J. Zhu, and, J. Y. Wang. 2002. A myogenic differentiation checkpoint activated by genotoxic stress. Nat. Genet. 32:585593.
161. Rehemtulla, A.,, C. A. Hamilton,, A. M. Chinnaiyan, and, V. M. Dixit. 1997. Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1). J. Biol. Chem. 272:2578325786.
162. Reinke, V., and, G. Lozano. 1997. The p53 targets mdm2 and Fas are not required as mediators of apoptosis in vivo. Oncogene 15:15271534.
163. Rich, T.,, R. L. Allen, and, A. H. Wyllie. 2000. Defying death after DNA damage. Nature 407:777783.
164. Robles, A. I.,, N. A. Bemmels,, A. B. Foraker, and, C. C. Harris. 2001. APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer Res. 61:66606664.
165. Rouse, J., 2004. Esc4p, a new target of Mec1p (ATR), promotes resumption of DNA synthesis after DNA damage. EMBO J. 23:11881197.
166. Rowan, S.,, R. L. Ludwig,, Y. Haupt,, S. Bates,, X. Lu,, M. Oren, and, K. H. Vousden. 1996. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 15:827838.
167. Russell, K. J.,, L. W. Wiens,, G. W. Demers,, D. A. Galloway,, S. E. Plon, and, M. Groudine. 1995. Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res. 55:16391642.
168. Sampath, D., and, W. Plunkett. 2001. Design of new anticancer therapies targeting cell cycle checkpoint pathways. Curr. Opin. Cell Biol. 13:484490.
169. Samuels-Lev, Y.,, D. J. O’Connor,, D. Bergamaschi,, G. Trigiante,, J. K. Hsieh,, S. Zhong,, I. Campargue,, L. Naumovski,, T. Crook, and, X. Lu. 2001. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8:781794.
170. Sandell, L. L., and, V. A. Zakian. 1993. Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell 75:729739.
171. Satyanarayana, A.,, R. A. Greenberg,, S. Schaetzlein,, J. Buer,, K. Masutomi,, W. C. Hahn,, S. Zimmermann,, U. Martens,, M. P. Manns, and, K. L. Rudolph., 2004. Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol. Cell. Biol. 24:5459–5474.
172. Screaton, R. A.,, S. Kiessling,, O. J. Sansom,, C. B. Millar,, K. Mad-dison,, A. Bird,, A. R. Clarke, and, S. M. Frisch. 2003. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis. Proc. Natl. Acad. Sci. USA 100:52115216.
173. Shafman, T.,, K. K. Khanna,, P. Kedar,, K. Spring,, S. Kozlov,, T. Yen,, K. Hobson,, M. Gatel,, N. Zhang,, D. Watters,, M. Egerton,, Y. Shiloh,, S. Kharbanda,, D. Kufe, and, M. F. Lavin. 1997. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387:520523.
174. Shaulian, E.,, M. Schreiber,, F. Piu,, M. Beeche,, E. F. Wagner, and, M. Karin. 2000. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell 103:897907.
175. Shi, Y., 2002. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell 9:459470.
176. Shibue, T.,, K. Takeda,, E. Oda,, H. Tanaka,, H. Murasawa,, A. Takaoka,, Y. Morishita,, S. Akira,, T. Taniguchi, and, N. Tanaka. 2003. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev. 17:22332238.
177. Singh, K. K.,, J. Russell,, B. Sigala,, Y. Zhang,, J. Williams, and, K. F. Keshav. 1999. Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene 18:66416646.
178. Slee, E. A.,, D. J. O’Connor, and, X. Lu. 2004. To die or not to die: how does p53 decide? Oncogene 23:28092818.
179. Slichenmyer, W. J.,, W. G. Nelson,, R. J. Slebos, and, M. B. Kastan. 1993. Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res. 53:41644168.
180. Sogame, N.,, M. Kim, and, J. M. Abrams. 2003. Drosophila p53 preserves genomic stability by regulating cell death. Proc. Natl. Acad. Sci. USA 100:46964701.
181. Stevens, C.,, L. Smith, and, N. B. La Thangue. 2003. Chk2 activates E2F-1 in response to DNA damage. Nat. Cell Biol. 5:401409.
182. Strasser, A.,, A. W. Harris,, T. Jacks, and, S. Cory. 1994. DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329339.
183. Strasser, A.,, L. O’Connor, and, V. Dixit. 2000. Apoptosis signaling. Annu. Rev. Biochem. 69:217245.
184. Takada, S.,, A. Kelkar, and, W. E. Theurkauf. 2003. Drosophila checkpoint kinase 2 couples centrosome function and spindle assembly to genomic integrity. Cell 113:8799.
185. Takai, H.,, K. Naka,, Y. Okada,, M. Watanabe,, N. Harada,, S. Saito,, C. W. Anderson,, E. Appella,, M. Nakanishi,, H. Suzuki,, K. Nagashima,, H. Sawa,, K. Ikeda, and, N. Motoyama. 2002. Chk2-deficient mice exhibit radioresistant and defective p53-mediated transcription. EMBO J. 21:51955205.
186. Tanikawa, C.,, K. Matsuda,, S. Fukuda,, Y. Nakamura, and, H. Arakawa. 2003. p53RDL1 regulates p53-dependent apoptosis. Nat. Cell Biol. 5:216223.
187. Tinel, A., and, J. Tschopp. 2004. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304:843846.
188. Toczyski, D. P.,, D. J. Galgoczy, and, L. H. Hartwell. 1997. CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Cell 90:10971106.
189. Tomei, L. D., and, F. O. Cope (ed.)., 1991. Apoptosis: the Molecular Basis of Cell Death, vol. 3. Cold Spring Harbor Laboratory Press, Plainview, N.Y.
190. Tyner, S. D.,, S. Venkatachalam,, J. Choi,, S. Jones,, N. Ghebran-ious,, H. Ingelmann,, X. Lu,, G. Soron,, B. Cooper,, C. Brayton,, S. H. Park,, T. Thompson,, G. Karsenty,, A. Bradley, and, L. A. Donehower. 2002. p53 mutant mice that display early ageing-associated phenotypes. Nature 415:4553.
191. Varfolomeev, E. E.,, M. Schuchmann,, V. Luria,, N. Chiannilkul-chai,, J. S. Beckmann,, I. L. Mett,, D. Rebrikov,, V. M. Brodianski,, O. C. Kemper,, O. Kollet,, T. Lapidot,, D. Soffer,, T. Sobe,, K. B. Avraham,, T. Goncharov,, H. Holtmann,, P. Lonai, and, D. Wallach. 1998. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267276.
192. Vaze, M. B.,, A. Pellicioli,, S. E. Lee,, G. Ira,, G. Liberi,, A. ArbelEden,, M. Foiani, and, J. E. Haber. 2002. Recovery from checkpoint-mediated arrest after repair of a double-strand break requires Srs2 helicase. Mol. Cell 10:373385.
193. Vaziri, H., and, S. Benchimol. 1999. Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase. Oncogene 18:76767680.
194. Villunger, A.,, E. Michalak,, L. Coultas,, F. Müllauer,, G. Böck,, M. Ausserlechner,, J. Adams, and, A. Strasser. 2003. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302:10361038.
195. Vossio, S.,, E. Palescandolo,, N. Pediconi,, F. Moretti,, C. Balsano,, M. Levrero, and, A. Costanzo. 2002. DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest. Oncogene 21:37963803.
196. Vousden, K. H., and, X. Lu. 2002. Live or let die: the cell’s response to p53. Nat. Rev. Cancer 2:594604.
197. Wang, C.-Y.,, M. W. Mayo,, R. G. Korneluk,, D. V. Goeddel, and, A. S. Baldwin, Jr., 1998. NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:16801683.
198. Wang, S.,, M. Guo,, H. Ouyang,, X. Li,, C. Cordon-Cardo,, A. Kuri-masa,, D. J. Chen,, Z. Fuks,, C. C. Ling, and, G. C. Li. 2000. The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest. Proc. Natl. Acad. Sci. USA 97:15841588.
199. Wang, X., 2001. The expanding role of mitochondria in apopto-sis. Genes Dev. 15:29222933.
200. Wang, Z. G.,, D. Ruggero,, S. Ronchetti,, S. Zhong,, M. Gaboli,, R. Rivi, and, P. P. Pandolfi. 1998. PML is essential for multiple apoptotic pathways. Nat. Genet. 20:266272.
201. Webley, K.,, J. A. Bond,, C. J. Jones,, J. P. Blaydes,, A. Craig,, T. Hupp, and, D. Wynford-Thomas. 2000. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol. 20:28032808.
202. Wechsler, T.,, B. P. Chen,, R. Harper,, K. Morotomi-Yano,, B. C. Huang,, K. Meek,, J. E. Cleaver,, D. J. Chen, and, M. Wabl. 2004. DNA-PKcs function regulated specifically by protein phosphatase 5. Proc. Natl. Acad. Sci. USA 101:12471252.
203. Westphal, C. H.,, S. Rowan,, C. Schmaltz,, A. Elson,, D. E. Fisher, and, P. Leder. 1997. atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat. Genet. 16:397401.
204. Wu, G. S.,, T. F. Burns,, E. R. McDonald III,, W. Jiang,, R. Meng,, I. D. Krantz,, G. Kao,, D.-D. Gan,, J.-Y. Zhou,, R. Muschel,, S. R. Hamilton,, N. B. Spinner,, S. Markowitz,, G. Wu, and, W. El-Deiry. 1997. KILLER/DR5is a DNA damage-inducible p53-regulated death receptor gene. Nat. Genet. 17:141143.
205. Wu, J.,, L. Gu,, H. Wang,, N. E. Geacintov, and, G.-M. Li. 1999. Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis. Mol. Cell. Biol. 19:82928301.
206. Wu, X., and, A. Levine. 1994. p53 and E2F-1 co-operate to mediate apoptosis. Proc. Natl. Acad. Sci. USA 91:36023606.
207. Xu, Z. X.,, A. Timanova-Atanasova,, R. X. Zhao, and, K. S. Chang. 2003. PML colocalizes with and stabilizes the DNA damage response protein TopBP1. Mol. Cell. Biol. 23:42474256.
208. Yamane, K.,, M. Kawabata, and, T. Tsuruo. 1997. A DNA-topoisomerase-II-binding protein with eight repeating regions similar to DNA-repair enzymes and to a cell-cycle regulator. Eur. J. Biochem. 250:794799.
209. Yamane, K.,, X. Wu, and, J. Chen. 2002. A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol. Cell. Biol. 22:555566.
210. Yang, A.,, M. Kaghad,, D. Caput, and, F. McKeon. 2002. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet. 18:9095.
211. Yang, A.,, M. Kaghad,, Y. Wang,, E. Gillett,, M. D. Fleming,, V. Dötsch,, N. C. Andrews,, D. Caput, and, F. McKeon. 1998. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2:305316.
212. Yang, A., and, F. McKeon. 2000. P63 and P73: P53 mimics, menaces and more. Nat. Rev. Mol. Cell Biol. 1:199207.
213. Yang, A.,, R. Schweitzer,, D. Sun,, M. Kaghad,, N. Walker,, R. T. Bronson,, C. Tabin,, A. Sharpe,, D. Caput,, C. Crum, and, F. McKeon. 1999. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714718.
214. Yang, A.,, N. Walker,, R. Bronson,, M. Kaghad,, M. Oosterwegel,, J. Bonnin,, C. Vagner,, H. Bonnet,, P. Dikkes,, A. Sharpe,, F. McKeon, and, D. Caput. 2000. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99103.
215. Yeh, W. C.,, J. L. Pompa,, M. E. McCurrach,, H. B. Shu,, A. J. Elia,, A. Shahinian,, M. Ng,, A. Wakeham,, W. Khoo,, K. Mitchell,, W. S. El-Deiry,, S. W. Lowe,, D. V. Goeddel, and, T. W. Mak. 1998. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279:19541958.
216. Yin, Y.,, A. Zhu,, Y. J. Jin,, Y. X. Liu,, X. Zhang,, K. M. Hopkins, and, H. B. Lieberman. 2004. Human RAD9 checkpoint control/proapoptotic protein can activate transcription of p21. Proc. Natl. Acad. Sci. USA 101:88648869.
217. Yoneda, M.,, K. Katsumata,, M. Hayakawa,, M. Tanaka, and, T. Ozawa. 1995. Oxygen stress induces an apoptotic cell death associated with fragmentation of mitochondrial genome. Biochem. Biophys. Res. Commun. 209:723729.
218. Yoshida, H.,, Y. Y. Kong,, R. Yoshida,, A. J. Elia,, A. Hakem,, R. Hakem,, J. M. Penninger, and, T. W. Mak. 1998. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739750.
219. Yoshida, K.,, K. Komatsu,, H.-G. Wang, and, D. Kufe. 2002. c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage. Mol. Cell. Biol. 22:32923300.
220. Yu, S. W.,, H. Wang,, M. F. Poitras,, C. Coombs,, W. J. Bowers,, H. J. Federoff,, G. G. Poirier,, T. M. Dawson, and, V. L. Dawson. 2002. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259263.
221. Yuan, Z.-M.,, H. Shioya,, T. Ishiko,, X. Sun,, J. Gu,, Y. Huang,, H. Lu,, S. Kharbanda,, R. Weichselbaum, and, D. Kufe. 1999. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399:814817.
222. Zhao, R.,, K. Gish,, M. Murphy,, Y. Yin,, D. Notterman,, W. H. Hoffman,, E. Tom,, D. H. Mack, and, A. J. Levine. 2000. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14:981993.
223. Zhou, B. B. S., and, J. Bartek. 2004. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat. Rev. Cancer 4:110.
224. Zong, W. X.,, D. Ditsworth,, D. E. Bauer,, Z. Q. Wang, and, C. B. Thompson. 2004. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18:12721282.
225. Zou, L., and, S. J. Elledge. 2003. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:15421548.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error