Cellular and Molecular Life Sciences

, Volume 67, Issue 21, pp 3609–3620 | Cite as

Posttranslational modification of mammalian AP endonuclease (APE1)

  • Carlos S. Busso
  • Michael W. Lake
  • Tadahide Izumi
Multi-Author Review


A key issue in studying mammalian DNA base excision repair is how its component proteins respond to a plethora of cell-signaling mediators invoked by DNA damage and stress-inducing agents such as reactive oxygen species, and how the actions of individual BER proteins are attributed to cell survival or apoptotic/necrotic death. This article reviews the past and recent progress on posttranslational modification (PTM) of mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1).


DNA base excision repair APE1 Phosphorylation Acetylation Ubiquitination 





AP endonuclease


AP endonuclease 1


Base excision repair


Casein kinase II


Flap endonuclease 1


Histone acetyltransferase


Histone deacetylase


Mouse double minute 2




Negative calcium response element




Poly(ADP-ribose) polymerase 1


Protein kinase C

Pol B

DNA polymerase beta


Redox factor 1


Reactive oxygen species


Single-strand break


Posttranslational modification


Single nucleotide polymorphism


Transcription factor


Trichostatin A


X-ray repair cross complementation group 1



While we were in the final process of revision, Huang et al. newly reported that APE1 was phosphorylated at Thr 233, resulting in a decrease of the APE activity, particularly in brain tissues from patients with Parkinson’s and Alzheimer’s diseases (Nat Cell Biol 12:563–571, 2010). A significant question in relation to this review is if and how T233 phosphorylation affects the intracellular levels of acetylated and ubiquitinated APE1. This work was supported by NIH CA98664 (TI).


  1. 1.
    Lindahl T, Barnes DE (2000) Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol 65:127–133PubMedGoogle Scholar
  2. 2.
    Evans MD, Dizdaroglu M, Cooke MS (2004) Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 567:1–61PubMedGoogle Scholar
  3. 3.
    Demple B, Johnson A, Fung D (1986) Exonuclease III and endonuclease IV remove 3’ blocks from DNA synthesis primers in H2O2-damaged Escherichia coli. Proc Natl Acad Sci USA 83:7731–7735PubMedGoogle Scholar
  4. 4.
    Izumi T, Hazra TK, Boldogh I, Tomkinson AE, Park MS, Ikeda S, Mitra S (2000) Requirement for human AP endonuclease 1 for repair of 3′-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Carcinogenesis 21:1329–1334PubMedGoogle Scholar
  5. 5.
    Izumi T, Wiederhold LR, Roy G, Roy R, Jaiswal A, Bhakat KK, Mitra S, Hazra TK (2003) Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage. Toxicology 193:43–65PubMedGoogle Scholar
  6. 6.
    Parsons JL, Dianova II, Dianov GL (2005) APE1-dependent repair of DNA single-strand breaks containing 3′-end 8-oxoguanine. Nucleic Acids Res 33:2204–2209PubMedGoogle Scholar
  7. 7.
    Koukourakis MI, Giatromanolaki A, Kakolyris S, Sivridis E, Georgoulias V, Funtzilas G, Hickson ID, Gatter KC, Harris AL (2001) Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome. Int J Radiat Oncol Biol Phys 50:27–36PubMedGoogle Scholar
  8. 8.
    Bobola MS, Finn LS, Ellenbogen RG, Geyer JR, Berger MS, Braga JM, Meade EH, Gross ME, Silber JR (2005) Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors. Clin Cancer Res 11:7405–7414PubMedGoogle Scholar
  9. 9.
    Bobola MS, Emond MJ, Blank A, Meade EH, Kolstoe DD, Berger MS, Rostomily RC, Silbergeld DL, Spence AM, Silber JR (2004) Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. Clin Cancer Res 10:7875–7883PubMedGoogle Scholar
  10. 10.
    Bobola MS, Blank A, Berger MS, Stevens BA, Silber JR (2001) Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas. Clin Cancer Res 7:3510–3518PubMedGoogle Scholar
  11. 11.
    Silber JR, Bobola MS, Blank A, Schoeler KD, Haroldson PD, Huynh MB, Kolstoe DD (2002) The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. Clin Cancer Res 8:3008–3018PubMedGoogle Scholar
  12. 12.
    Parsons JL, Tait PS, Finch D, Dianova II, Allinson SL, Dianov GL (2008) CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins. Mol Cell 29:477–487PubMedGoogle Scholar
  13. 13.
    Parsons JL, Tait PS, Finch D, Dianova II, Edelmann MJ, Khoronenkova SV, Kessler BM, Sharma RA, McKenna WG, Dianov GL (2009) Ubiquitin ligase ARF-BP1/Mule modulates base excision repair. EMBO J 28:3207–3215PubMedGoogle Scholar
  14. 14.
    Wilson SH, Kunkel TA (2000) Passing the baton in base excision repair. Nat Struct Biol 7:176–178PubMedGoogle Scholar
  15. 15.
    Ha HC, Snyder SH (1999) Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 96:13978–13982PubMedGoogle Scholar
  16. 16.
    Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095PubMedGoogle Scholar
  17. 17.
    Peddi SR, Chattopadhyay R, Naidu CV, Izumi T (2006) The human apurinic/apyrimidinic endonuclease-1 suppresses activation of poly(adp-ribose) polymerase-1 induced by DNA single strand breaks. Toxicology 224:44–55PubMedGoogle Scholar
  18. 18.
    Prasad R, Liu Y, Deterding LJ, Poltoratsky VP, Kedar PS, Horton JK, Kanno S, Asagoshi K, Hou EW, Khodyreva SN, Lavrik OI, Tomer KB, Yasui A, Wilson SH (2007) HMGB1 is a cofactor in mammalian base excision repair. Mol Cell 27:829–841PubMedGoogle Scholar
  19. 19.
    Vidal AE, Boiteux S, Hickson ID, Radicella JP (2001) XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein–protein interactions. EMBO J S 20:6530–6539Google Scholar
  20. 20.
    Marsin S, Vidal AE, Sossou M, Menissier-de Murcia J, Le Page F, Boiteux S, de Murcia G, Radicella JP (2003) Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1. J Biol Chem 278:44068–44074PubMedGoogle Scholar
  21. 21.
    Bennett RA, Wilson DMr, Wong D, Demple B (1997) Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci USA 94:7166–7169PubMedGoogle Scholar
  22. 22.
    Zhou J, Ahn J, Wilson SH, Prives C (2001) A role for p53 in base excision repair. EMBO J 20:914–923PubMedGoogle Scholar
  23. 23.
    Meira LB, Cheo DL, Hammer RE, Burns DK, Reis A, Friedberg EC (1997) Genetic interaction between HAP1/REF-1 and p53. Nat Genet 17:145PubMedGoogle Scholar
  24. 24.
    Xanthoudakis S, Miao G, Wang F, Pan YC, Curran T (1992) Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. EMBO J 11:3323–3335PubMedGoogle Scholar
  25. 25.
    Okazaki T, Chung U, Nishishita T, Ebisu S, Usuda S, Mishiro S, Xanthoudakis S, Igarashi T, Ogata E (1994) A redox factor protein, ref1, is involved in negative gene regulation by extracellular calcium. J Biol Chem 269:27855–27862PubMedGoogle Scholar
  26. 26.
    Evans AR, Limp-Foster M, Kelley MR (2000) Going APE over ref-1. Mutat Res 461:83–108PubMedGoogle Scholar
  27. 27.
    Ray S, Lee C, Hou T, Bhakat KK, Brasier AR (2010) Regulation of signal transducer and activator of transcription 3 enhanceosome formation by apurinic/apyrimidinic endonuclease 1 in hepatic acute phase response. Mol Endocrinol 24:391–401PubMedGoogle Scholar
  28. 28.
    Chattopadhyay R, Das S, Maiti AK, Boldogh I, Xie J, Hazra TK, Kohno K, Mitra S, Bhakat KK (2008) Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1. Mol Cell Biol 28:7066–7080PubMedGoogle Scholar
  29. 29.
    Xanthoudakis S, Miao GG, Curran T (1994) The redox and DNA-repair activities of Ref-1 are encoded by nonoverlapping domains. Proc Natl Acad Sci USA 91:23–27PubMedGoogle Scholar
  30. 30.
    Georgiadis MM, Luo M, Gaur RK, Delaplane S, Li X, Kelley MR (2008) Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease. Mutat Res 643:54–63PubMedGoogle Scholar
  31. 31.
    Demple B, Herman T, Chen DS (1991) Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes. Proc Natl Acad Sci USA 88:11450–11454PubMedGoogle Scholar
  32. 32.
    Robson CN, Milne AM, Pappin DJ, Hickson ID (1991) Isolation of cDNA clones encoding an enzyme from bovine cells that repairs oxidative DNA damage in vitro: homology with bacterial repair enzymes. Nucleic Acids Res 19:1087–1092PubMedGoogle Scholar
  33. 33.
    Seki S, Hatsushika M, Watanabe S, Akiyama K, Nagao K, Tsutsui K (1992) cDNA cloning, sequencing, expression and possible domain structure of human APEX nuclease homologous to Escherichia coli exonuclease III. Biochim Biophys Acta 1131:287–299PubMedGoogle Scholar
  34. 34.
    Johnson RE, Torres-Ramos CA, Izumi T, Mitra S, Prakash S, Prakash L (1998) Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites. Genes Dev 12:3137–3143PubMedGoogle Scholar
  35. 35.
    Xanthoudakis S, Smeyne RJ, Wallace JD, Curran T (1996) The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proc Natl Acad Sci USA 93:8919–8923PubMedGoogle Scholar
  36. 36.
    Izumi T, Brown DB, Naidu CV, Bhakat KK, Macinnes MA, Saito H, Chen DJ, Mitra S (2005) Two essential but distinct functions of the mammalian abasic endonuclease. Proc Natl Acad Sci USA 102:5739–5743PubMedGoogle Scholar
  37. 37.
    Fung H, Demple B (2005) A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. Mol Cell 17:463–470PubMedGoogle Scholar
  38. 38.
    Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S (2003) Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. EMBO J 22:6299–6309PubMedGoogle Scholar
  39. 39.
    Vascotto C, Fantini D, Romanello M, Cesaratto L, Deganuto M, Leonardi A, Radicella JP, Kelley MR, D’Ambrosio C, Scaloni A, Quadrifoglio F, Tell G (2009) APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process. Mol Cell Biol 29:1834–1854PubMedGoogle Scholar
  40. 40.
    Tell G, Quadrifoglio F, Tiribelli C, Kelley MR (2008) The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxid Redox Signal 11:601–620Google Scholar
  41. 41.
    Hadi MZ, Coleman MA, Fidelis K, Mohrenweiser HW, Wilson DM 3rd (2000) Functional characterization of Ape1 variants identified in the human population. Nucleic Acids Res 28:3871–3879PubMedGoogle Scholar
  42. 42.
    Daviet S, Couve-Privat S, Gros L, Shinozuka K, Ide H, Saparbaev M, Ishchenko AA (2007) Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway. DNA Repair (Amst) 6:8–18Google Scholar
  43. 43.
    Hu JJ, Smith TR, Miller MS, Mohrenweiser HW, Golden A, Case LD (2001) Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis 22:917–922PubMedGoogle Scholar
  44. 44.
    Hu JJ, Smith TR, Miller MS, Lohman K, Case LD (2002) Genetic regulation of ionizing radiation sensitivity and breast cancer risk. Environ Mol Mutagen 39:208–215PubMedGoogle Scholar
  45. 45.
    Jiao L, Bondy ML, Hassan MM, Wolff RA, Evans DB, Abbruzzese JL, Li D (2006) Selected polymorphisms of DNA repair genes and risk of pancreatic cancer. Cancer Detect Prev 30:284–291PubMedGoogle Scholar
  46. 46.
    Yacoub A, Kelley MR, Deutsch WA (1997) The DNA repair activity of human redox/repair protein APE/Ref-1 is inactivated by phosphorylation. Cancer Res 57:5457–5459PubMedGoogle Scholar
  47. 47.
    Fritz G, Kaina B (1999) Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1. Oncogene 18:1033–1040PubMedGoogle Scholar
  48. 48.
    Hsieh MM, Hegde V, Kelley MR, Deutsch WA (2001) Activation of APE/Ref-1 redox activity is mediated by reactive oxygen species and PKC phosphorylation. Nucleic Acids Res 29:3116–3122PubMedGoogle Scholar
  49. 49.
    Mckenzie JA, Strauss PR (2003) A quantitative method for measuring protein phosphorylation. Anal Biochem 313:9–16PubMedGoogle Scholar
  50. 50.
    Qu J, Liu GH, Huang B, Chen C (2007) Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of cysteines 93 and 310. Nucleic Acids Res 35:2522–2532PubMedGoogle Scholar
  51. 51.
    Kakolyris S, Kaklamanis L, Giatromanolaki A, Koukourakis M, Hickson ID, Barzilay G, Turley H, Leek RD, Kanavaros P, Georgoulias V, Gatter KC, Harris AL (1998) Expression and subcellular localization of human AP endonuclease 1 (HAP1/Ref-1) protein: a basis for its role in human disease. Histopathology 33:561–569PubMedGoogle Scholar
  52. 52.
    Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, Jung SB, Kim CS, Irani K (2010) SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res 38:832–845PubMedGoogle Scholar
  53. 53.
    Vo N, Goodman RH (2001) CREB-binding protein and p300 in transcriptional regulation. J Biol Chem 276:13505–13508PubMedGoogle Scholar
  54. 54.
    Bhakat KK, Mantha AK, Mitra S (2009) Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxid Redox Signal 11:621–638PubMedGoogle Scholar
  55. 55.
    Fuchs S, Philippe J, Corvol P, Pinet F (2003) Implication of Ref-1 in the repression of renin gene transcription by intracellular calcium. J Hypertens 21:327–335PubMedGoogle Scholar
  56. 56.
    Bhakat KK, Hazra TK, Mitra S (2004) Acetylation of the human DNA glycosylase NEIL2 and inhibition of its activity. Nucleic Acids Res 32:3033–3039PubMedGoogle Scholar
  57. 57.
    Bhakat KK, Mokkapati SK, Boldogh I, Hazra TK, Mitra S (2006) Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo. Mol Cell Biol 26:1654–1665PubMedGoogle Scholar
  58. 58.
    Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, Yang WL, Wang J, Egia A, Nakayama KI, Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PP (2010) Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464:374–379PubMedGoogle Scholar
  59. 59.
    Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381PubMedGoogle Scholar
  60. 60.
    Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, Varshavsky A (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243:1576–1583PubMedGoogle Scholar
  61. 61.
    Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786PubMedGoogle Scholar
  62. 62.
    Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25–27PubMedGoogle Scholar
  63. 63.
    Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275:8945–8951PubMedGoogle Scholar
  64. 64.
    Mayo LD, Turchi JJ, Berberich SJ (1997) Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res 57:5013–5016PubMedGoogle Scholar
  65. 65.
    Shieh SY, Ikeda M, Taya Y, Prives C (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91:325–334PubMedGoogle Scholar
  66. 66.
    Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7:1126–1132PubMedGoogle Scholar
  67. 67.
    Midgley CA, Desterro JM, Saville MK, Howard S, Sparks A, Hay RT, Lane DP (2000) An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene 19:2312–2323PubMedGoogle Scholar
  68. 68.
    Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19:94–102PubMedGoogle Scholar
  69. 69.
    Pickart CM (2000) Ubiquitin in chains. Trends Biochem Sci 25:544–548PubMedGoogle Scholar
  70. 70.
    Marchenko ND, Wolff S, Erster S, Becker K, Moll UM (2007) Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 26:923–934PubMedGoogle Scholar
  71. 71.
    Taniguchi T, D’Andrea AD (2006) Molecular pathogenesis of Fanconi anemia: recent progress. Blood 107:4223–4233PubMedGoogle Scholar
  72. 72.
    Alpi AF, Pace PE, Babu MM, Patel KJ (2008) Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell 32:767–777PubMedGoogle Scholar
  73. 73.
    Spence J, Sadis S, Haas AL, Finley D (1995) A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol 15:1265–1273PubMedGoogle Scholar
  74. 74.
    Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135–141PubMedGoogle Scholar
  75. 75.
    Busso CS, Iwakuma T, Izumi T (2009) Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene 28:1616–1625PubMedGoogle Scholar
  76. 76.
    Kerscher O, Felberbaum R, Hochstrasser M (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol 22:159–180PubMedGoogle Scholar
  77. 77.
    Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848PubMedGoogle Scholar
  78. 78.
    Li W, Ye Y (2008) Polyubiquitin chains: functions, structures, and mechanisms. Cell Mol Life Sci 65:2397–2406PubMedGoogle Scholar
  79. 79.
    Cadwell K, Coscoy L (2005) Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science 309:127–130PubMedGoogle Scholar
  80. 80.
    Bartel B, Wunning I, Varshavsky A (1990) The recognition component of the N-end rule pathway. EMBO J 9:3179–3189PubMedGoogle Scholar
  81. 81.
    Haas AL, Siepmann TJ (1997) Pathways of ubiquitin conjugation. FASEB J 11:1257–1268PubMedGoogle Scholar
  82. 82.
    Gorman MA, Morera S, Rothwell DG, de La Fortelle E, Mol CD, Tainer JA, Hickson ID, Freemont PS (1997) The crystal structure of the human DNA repair endonuclease HAP1 suggests the recognition of extra-helical deoxyribose at DNA abasic sites. EMBO J 16:6548–6558PubMedGoogle Scholar
  83. 83.
    Mol CD, Izumi T, Mitra S, Tainer JA (2000) DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected]. Nature 403:451–456PubMedGoogle Scholar
  84. 84.
    Izumi T, Mitra S (1998) Deletion analysis of human AP-endonuclease: minimum sequence required for the endonuclease activity. Carcinogenesis 19:525–527PubMedGoogle Scholar
  85. 85.
    Jackson EB, Theriot CA, Chattopadhyay R, Mitra S, Izumi T (2005) Analysis of nuclear transport signals in the human apurinic/apyrimidinic endonuclease (APE1/Ref1). Nucleic Acids Res 33:3303–3312PubMedGoogle Scholar
  86. 86.
    Hurley JH, Lee S, Prag G (2006) Ubiquitin-binding domains. Biochem J 399:361–372PubMedGoogle Scholar
  87. 87.
    Vascotto C, Cesaratto L, Zeef LA, Deganuto M, D’Ambrosio C, Scaloni A, Romanello M, Damante G, Taglialatela G, Delneri D, Kelley MR, Mitra S, Quadrifoglio F, Tell G (2009) Genome-wide analysis and proteomic studies reveal APE1/Ref-1 multifunctional role in mammalian cells. Proteomics 9:1058–1074PubMedGoogle Scholar
  88. 88.
    Zhao J, Gao F, Zhang Y, Wei K, Liu Y, Deng X (2008) Bcl2 inhibits abasic site repair by down-regulating APE1 endonuclease activity. J Biol Chem 283:9925–9932Google Scholar
  89. 89.
    Karni-Schmidt O, Zupnick A, Castillo M, Ahmed A, Matos T, Bouvet P, Cordon-Cardo C, Prives C (2008) p53 is localized to a sub-nucleolar compartment after proteasomal inhibition in an energy-dependent manner. J Cell Sci 121:4098–4105PubMedGoogle Scholar
  90. 90.
    Tao W, Levine AJ (1999) Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci USA 96:3077–3080PubMedGoogle Scholar
  91. 91.
    Roth J, Dobbelstein M, Freedman DA, Shenk T, Levine AJ (1998) Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J 17:554–564PubMedGoogle Scholar
  92. 92.
    Stetler RA, Gao Y, Zukin RS, Vosler PS, Zhang L, Zhang F, Cao G, Bennett MV, Chen J (2010) Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. Proc Natl Acad Sci USA 107:3204–3209PubMedGoogle Scholar
  93. 93.
    Vaupel P, Hockel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9:1221–1235PubMedGoogle Scholar
  94. 94.
    Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302:1972–1975PubMedGoogle Scholar
  95. 95.
    Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O’Rourke K, Koeppen H, Dixit VM (2004) The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429:86–92PubMedGoogle Scholar
  96. 96.
    Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112:779–791PubMedGoogle Scholar
  97. 97.
    Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W (2002) Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416:648–653PubMedGoogle Scholar
  98. 98.
    Cummins JM, Rago C, Kohli M, Kinzler KW, Lengauer C, Vogelstein B (2004) Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 428:486Google Scholar
  99. 99.
    Badciong JC, Haas AL (2002) MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination. J Biol Chem 277:49668–49675PubMedGoogle Scholar
  100. 100.
    Fujimuro M, Sawada H, Yokosawa H (1994) Production and characterization of monoclonal antibodies specific to multi-ubiquitin chains of polyubiquitinated proteins. FEBS Lett 349:173–180PubMedGoogle Scholar
  101. 101.
    Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274:948–953PubMedGoogle Scholar
  102. 102.
    Cheng Q, Chen L, Li Z, Lane WS, Chen J (2009) ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 28:3857–3867PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Carlos S. Busso
    • 1
  • Michael W. Lake
    • 1
  • Tadahide Izumi
    • 1
  1. 1.Department of Otorhinolaryngology and Stanley S. Scott Cancer CenterLouisiana State University Health Sciences CenterNew OrleansUSA

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