Skip to main content

Advertisement

SpringerLink
Log in

Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment

  • Multi-Author Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The apurinic endonuclease 1/redox factor-1 (APE1) has a crucial function in DNA repair and in redox signaling in mammals, and recent studies identify it as an excellent target for sensitizing tumor cells to chemotherapy. APE1 is an essential enzyme in the base excision repair pathway of DNA lesions caused by oxidation and alkylation. As importantly, APE1 also functions as a redox agent maintaining transcription factors involved in cancer promotion and progression in an active reduced state. Very recently, a new unsuspected function of APE1 in RNA metabolism was discovered, opening new perspectives for this multifunctional protein. These observations underline the necessity to understand the molecular mechanisms responsible for fine-tuning its different biological functions. This survey intends to give an overview of the multifunctional roles of APE1 and their regulation in the context of considering this protein a promising tool for anticancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

8-OHG:

8-Hydroxyguanine

AP:

Apurinic/apyrimidinic

AP-1:

Activating Protein-1

APE1:

Apurinic apyrimidinic endonuclease 1

BER:

Base excision repair

CKI and CKII:

Casein kinase I and II

CREB:

cAMP-responsible element binding protein

Egr-1:

Early growth response protein-1

FEN1:

Flap endonuclease I

GSK3:

Glycogen synthase kinase 3

GzmA:

Granzyme A

GzmK:

Granzyme K

HIF-1α:

Hypoxia inducible factor-1α

MTS:

Mitochondrial targeting sequence

MPG:

Methylpurine DNA glycosylase

MYH:

Human MutY glycosylase homolog

NF-κB:

Nuclear factor-kappaB

nCaRE:

Negative calcium responsive elements

NLS:

Nuclear localization signal

NPM1:

Nucleophosmin 1

OGG-1:

8-Oxoguanine DNA glycosylase

PARP-1:

Poly(ADP-ribose) polymerase

Pax:

Paired box-containing proteins

PCNA:

Proliferating cell nuclear antigen

PEBP-2:

Polyoma virus enhancer-binding protein-2

PKC:

Protein kinase C

Polβ:

Polymerase β

PTEN:

Phosphatase and tensin homolog

PTH:

Parathyroid hormone

PTM:

Post-translational modification

RFC:

Replication factor C

ROS:

Reactive oxygen species

Trx:

Thioredoxin

XRCC1:

X-ray cross-species complementing 1

References

  1. Fung H, Demple B (2005) A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells. Mol Cell 17:463–470

    Article  PubMed  CAS  Google Scholar 

  2. Tell G, Damante G, Caldwell D, Kelley MR (2005) The intracellular localization of APE1/Ref-1: more than a passive phenomenon? Antioxid Redox Signal 7:367–384

    Article  PubMed  CAS  Google Scholar 

  3. O’Hara AM, Bhattacharyya A, Bai J, Mifflin RC, Ernst PB, Mitra S, Crowe SE (2009) Tumor necrosis factor (TNF)-alpha-induced IL-8 expression in gastric epithelial cells: role of reactive oxygen species and AP endonuclease-1/redox factor (Ref)-1. Cytokine 46:359–369

    Article  PubMed  CAS  Google Scholar 

  4. Chung U, Igarashi T, Nishishita T, Iwanari H, Iwamatsu A, Suwa A, Mimori T, Hata K, Ebisu S, Ogata E, Fujita T, Okazaki T (1996) The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium. J Biol Chem 271:8593–8598

    Article  PubMed  CAS  Google Scholar 

  5. Kuninger DT, Izumi T, Papaconstantinou J, Mitra S (2002) Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter. Nucleic Acids Res 30:823–829

    Article  PubMed  CAS  Google Scholar 

  6. 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 91:23–27

    Article  PubMed  CAS  Google Scholar 

  7. 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 29:1834–1854

    Article  PubMed  CAS  Google Scholar 

  8. Tell G, Wilson DM III, Lee CH (2010) Intrusion of a DNA repair protein in the RNome world: is this the beginning of a new era? Mol Cell Biol 30:366–371

    Google Scholar 

  9. Barnes T, Kim WC, Mantha AK, Kim SE, Izumi T, Mitra S, Lee CH (2009) Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA. Nucleic Acids Res 37:3946–3958

    Article  PubMed  CAS  Google Scholar 

  10. 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 9:1058–1074

    Article  PubMed  CAS  Google Scholar 

  11. 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 102:5739–5743

    Article  PubMed  CAS  Google Scholar 

  12. Chattopadhyay R, Wiederhold L, Szczesny B, Boldogh I, Hazra TK, Izumi T, Mitra S (2006) Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells. Nucleic Acids Res 34:2067–2076

    Article  PubMed  CAS  Google Scholar 

  13. Beernink PT, Segelke BW, Hadi MZ, Erzberger JP, Wilson DM III, Rupp B (2001) Two divalent metal ions in the active site of a new crystal form of human apurinic/apyrimidinic endonuclease, Ape1: implications for the catalytic mechanism. J Mol Biol 307:1023–1034

    Article  PubMed  CAS  Google Scholar 

  14. 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 16:6548–6558

    Article  PubMed  CAS  Google Scholar 

  15. Takeuchi R, Ruike T, Nakamura R, Shimanouchi K, Kanai Y, Abe Y, Ihara A, Sakaguchi K (2006) Drosophila DNA polymerase zeta interacts with recombination repair protein 1, the Drosophila homologue of human abasic endonuclease 1. J Biol Chem 281:11577–11585

    Article  PubMed  CAS  Google Scholar 

  16. 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 33:561–569

    Article  PubMed  CAS  Google Scholar 

  17. Bobola MS, Blank A, Berger MS, Stevens BA, Silber JR (2001) Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas. Clin Cancer Res 7:3510–3518

    PubMed  CAS  Google Scholar 

  18. Robertson KA, Bullock HA, Xu Y, Tritt R, Zimmerman E, Ulbright TM, Foster RS, Einhorn LH, Kelley MR (2001) Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Res 61:2220–2225

    PubMed  CAS  Google Scholar 

  19. Rossi O, Carrozzino F, Cappelli E, Carli F, Frosina G (2000) Analysis of repair of abasic sites in early onset breast cancer patients. Int J Cancer 85:21–26

    Article  PubMed  CAS  Google Scholar 

  20. Zou GM, Luo MH, Reed A, Kelley MR, Yoder MC (2007) Ape1 regulates hematopoietic differentiation of embryonic stem cells through its redox functional domain. Blood 109:1917–1922

    Article  PubMed  CAS  Google Scholar 

  21. Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G (2008) APE1/Ref-1 regulates PTEN expression mediated by Egr-1. Free Radic Res 42:20–29

    Article  PubMed  CAS  Google Scholar 

  22. 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 22:6299–6309

    Article  PubMed  CAS  Google Scholar 

  23. Parlanti E, Locatelli G, Maga G, Dogliotti E (2007) Human base excision repair complex is physically associated to DNA replication and cell cycle regulatory proteins. Nucleic Acids Res 35:1569–1577

    Article  PubMed  CAS  Google Scholar 

  24. Yu E, Gaucher SP, Hadi MZ (2010) Probing conformational changes in Ape1 during the progression of base excision repair. Biochemistry 49:3786–3796

    Article  PubMed  CAS  Google Scholar 

  25. Jayaraman L, Murthy KG, Zhu C, Curran T, Xanthoudakis S, Prives C (1997) Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes Dev 11:558–570

    Article  PubMed  CAS  Google Scholar 

  26. Xanthoudakis S, Curran T (1992) Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity. EMBO J 11:653–665

    PubMed  CAS  Google Scholar 

  27. Walker LJ, Robson CN, Black E, Gillespie D, Hickson ID (1993) Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding. Mol Cell Biol 13:5370–5376

    PubMed  CAS  Google Scholar 

  28. 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 643:54–63

    PubMed  CAS  Google Scholar 

  29. Ordway JM, Eberhart D, Curran T (2003) Cysteine 64 of Ref-1 is not essential for redox regulation of AP-1 DNA binding. Mol Cell Biol 23:4257–4266

    Article  PubMed  CAS  Google Scholar 

  30. Rothwell DG, Hickson ID (1996) Asparagine 212 is essential for abasic site recognition by the human DNA repair endonuclease HAP1. Nucleic Acids Res 24:4217–4221

    Article  PubMed  CAS  Google Scholar 

  31. 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 403:451–456

    Article  PubMed  CAS  Google Scholar 

  32. Barzilay G, Mol CD, Robson CN, Walker LJ, Cunningham RP, Tainer JA, Hickson ID (1995) Identification of critical active-site residues in the multifunctional human DNA repair enzyme HAP1. Nat Struct Biol 2:561–568

    Article  PubMed  CAS  Google Scholar 

  33. Hegde ML, Hazra TK, Mitra S (2008) Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res 18:27–47

    Article  PubMed  CAS  Google Scholar 

  34. Fortini P, Pascucci B, Parlanti E, D’Errico M, Simonelli V, Dogliotti E (2003) The base excision repair: mechanisms and its relevance for cancer susceptibility. Biochimie 85:1053–1071

    Article  PubMed  CAS  Google Scholar 

  35. Flaherty DM, Monick MM, Carter AB, Peterson MW, Hunninghake GW (2002) Oxidant-mediated increases in redox factor-1 nuclear protein and activator protein-1 DNA binding in asbestos-treated macrophages. J Immunol 168:5675–5681

    PubMed  CAS  Google Scholar 

  36. 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 193:43–65

    Article  PubMed  CAS  Google Scholar 

  37. Caldecott KW, Aoufouchi S, Johnson P, Shall S (1996) XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular ‘nick-sensor’ in vitro. Nucleic Acids Res 24:4387–4394

    Article  PubMed  CAS  Google Scholar 

  38. Liu H, Colavitti R, Rovira II, Finkel T (2005) Redox-dependent transcriptional regulation. Circ Res 97:967–974

    Article  PubMed  CAS  Google Scholar 

  39. Moran LK, Gutteridge JM, Quinlan GJ (2001) Thiols in cellular redox signalling and control. Curr Med Chem 8:763–772

    PubMed  CAS  Google Scholar 

  40. Nishi T, Shimizu N, Hiramoto M, Sato I, Yamaguchi Y, Hasegawa M, Aizawa S, Tanaka H, Kataoka K, Watanabe H, Handa H (2002) Spatial redox regulation of a critical cysteine residue of NF-kappa B in vivo. J Biol Chem 277:44548–44556

    Article  PubMed  CAS  Google Scholar 

  41. 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 11:3323–3335

    PubMed  CAS  Google Scholar 

  42. Huang RP, Adamson ED (1993) Characterization of the DNA-binding properties of the early growth response-1 (Egr-1) transcription factor: evidence for modulation by a redox mechanism. DNA Cell Biol 12:265–273

    Article  PubMed  CAS  Google Scholar 

  43. Gaiddon C, Moorthy NC, Prives C (1999) Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo. EMBO J 18:5609–5621

    Article  PubMed  CAS  Google Scholar 

  44. Tell G, Pellizzari L, Cimarosti D, Pucillo C, Damante G (1998) Ref-1 controls pax-8 DNA-binding activity. Biochem Biophys Res Commun 252:178–183

    Article  PubMed  CAS  Google Scholar 

  45. Tell G, Pines A, Paron I, D’Elia A, Bisca A, Kelley MR, Manzini G, Damante G (2002) Redox effector factor-1 regulates the activity of thyroid transcription factor 1 by controlling the redox state of the N transcriptional activation domain. J Biol Chem 277:14564–14574

    Article  PubMed  CAS  Google Scholar 

  46. Tell G, Quadrifoglio F, Tiribelli C, Kelley MR (2009) The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxid Redox Signal 11:601–620

    Article  PubMed  CAS  Google Scholar 

  47. Ando K, Hirao S, Kabe Y, Ogura Y, Sato I, Yamaguchi Y, Wada T, Handa H (2008) A new APE1/Ref-1-dependent pathway leading to reduction of NF-kappaB and AP-1, and activation of their DNA-binding activity. Nucleic Acids Res 36:4327–4336

    Article  PubMed  CAS  Google Scholar 

  48. Angkeow P, Deshpande SS, Qi B, Liu YX, Park YC, Jeon BH, Ozaki M, Irani K (2002) Redox factor-1: an extra-nuclear role in the regulation of endothelial oxidative stress and apoptosis. Cell Death Differ 9:717–725

    Article  PubMed  CAS  Google Scholar 

  49. Bokoch GM, Diebold BA (2002) Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 100:2692–2696

    Article  PubMed  CAS  Google Scholar 

  50. Mohazzab KM, Wolin MS (1994) Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary artery PO2 sensor. Am J Physiol 267:L823–L831

    PubMed  CAS  Google Scholar 

  51. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M (2000) Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 20:2175–2183

    PubMed  CAS  Google Scholar 

  52. Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264:85–97

    Article  PubMed  CAS  Google Scholar 

  53. Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G (2002) Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 22:300–305

    Article  PubMed  CAS  Google Scholar 

  54. Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R (1997) Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation 96:2361–2367

    PubMed  CAS  Google Scholar 

  55. Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, Morawietz H (2000) Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun 269:713–717

    Article  PubMed  CAS  Google Scholar 

  56. Hwang J, Saha A, Boo YC, Sorescu GP, McNally JS, Holland SM, Dikalov S, Giddens DP, Griendling KK, Harrison DG, Jo H (2003) Oscillatory shear stress stimulates endothelial production of O2- from p47phox-dependent NAD(P)H oxidases, leading to monocyte adhesion. J Biol Chem 278:47291–47298

    Article  PubMed  CAS  Google Scholar 

  57. Patil S, Bunderson M, Wilham J, Black SM (2004) Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol 287:L1314–L1322

    Article  PubMed  CAS  Google Scholar 

  58. Rinckel LA, Faris SL, Hitt ND, Kleinberg ME (1999) Rac1 disrupts p67phox/p40phox binding: a novel role for Rac in NADPH oxidase activation. Biochem Biophys Res Commun 263:118–122

    Article  PubMed  CAS  Google Scholar 

  59. Fishel ML, Kelley MR (2007) The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. Mol Aspects Med 28:375–395

    Article  PubMed  CAS  Google Scholar 

  60. Zou GM, Maitra A (2008) Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration. Mol Cancer Ther 7:2012–2021

    Article  PubMed  CAS  Google Scholar 

  61. Lee JK, Edderkaoui M, Truong P, Ohno I, Jang KT, Berti A, Pandol SJ, Gukovskaya AS (2007) NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology 133:1637–1648

    Article  PubMed  CAS  Google Scholar 

  62. 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 269:27855–27862

    PubMed  CAS  Google Scholar 

  63. Mallette LE (1989) Regulation of blood calcium in humans. Endocrinol Metab Clin North Am 18:601–610

    PubMed  CAS  Google Scholar 

  64. Yamamoto M, Igarashi T, Muramatsu M, Fukagawa M, Motokura T, Ogata E (1989) Hypocalcemia increases and hypercalcemia decreases the steady-state level of parathyroid hormone messenger RNA in the rat. J Clin Invest 83:1053–1056

    Article  PubMed  CAS  Google Scholar 

  65. 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 21:327–335

    Article  PubMed  CAS  Google Scholar 

  66. Izumi T, Henner WD, Mitra S (1996) Negative regulation of the major human AP-endonuclease, a multifunctional protein. Biochemistry 35:14679–14683

    Article  PubMed  CAS  Google Scholar 

  67. Barzilay G, Walker LJ, Robson CN, Hickson ID (1995) Site-directed mutagenesis of the human DNA repair enzyme HAP1: identification of residues important for AP endonuclease and RNase H activity. Nucleic Acids Res 23:1544–1550

    Article  PubMed  CAS  Google Scholar 

  68. 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 28:7066–7080

    Article  PubMed  CAS  Google Scholar 

  69. Berquist BR, McNeill DR, Wilson DM III (2008) Characterization of abasic endonuclease activity of human Ape1 on alternative substrates, as well as effects of ATP and sequence context on AP site incision. J Mol Biol 379:17–27

    Google Scholar 

  70. Marenstein DR, Wilson DM III, Teebor GW (2004) Human AP endonuclease (APE1) demonstrates endonucleolytic activity against AP sites in single-stranded DNA. DNA Repair (Amst) 3:527–533

    Article  CAS  Google Scholar 

  71. Hofer T, Badouard C, Bajak E, Ravanat JL, Mattsson A, Cotgreave IA (2005) Hydrogen peroxide causes greater oxidation in cellular RNA than in DNA. Biol Chem 386:333–337

    Article  PubMed  CAS  Google Scholar 

  72. Shan X, Chang Y, Lin CL (2007) Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression. FASEB J 21:2753–2764

    Article  PubMed  CAS  Google Scholar 

  73. 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 93:8919–8923

    Article  PubMed  CAS  Google Scholar 

  74. Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999) Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 19:495–501

    Article  PubMed  CAS  Google Scholar 

  75. Guan Z, Basi D, Li Q, Mariash A, Xia YF, Geng JG, Kao E, Hall JL (2005) Loss of redox factor 1 decreases NF-kappaB activity and increases susceptibility of endothelial cells to apoptosis. Arterioscler Thromb Vasc Biol 25:96–101

    PubMed  CAS  Google Scholar 

  76. Evans AR, Limp-Foster M, Kelley MR (2000) Going APE over ref-1. Mutat Res 461:83–108

    PubMed  CAS  Google Scholar 

  77. Al-Attar A, Gossage L, Fareed KR, Shehata M, Mohammed M, Zaitoun AM, Soomro I, Lobo DN, Abbotts R, Chan S, Madhusudan S (2010) Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers. Br J Cancer 102:704–709

    Google Scholar 

  78. 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 8:3008–3018

    PubMed  CAS  Google Scholar 

  79. Ramana CV, Boldogh I, Izumi T, Mitra S (1998) Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc Natl Acad Sci USA 95:5061–5066

    Article  PubMed  CAS  Google Scholar 

  80. Chiarini LB, Freitas FG, Petrs-Silva H, Linden R (2000) Evidence that the bifunctional redox factor/AP endonuclease Ref-1 is an anti-apoptotic protein associated with differentiation in the developing retina. Cell Death Differ 7:272–281

    Article  PubMed  CAS  Google Scholar 

  81. Yoshida A, Urasaki Y, Waltham M, Bergman AC, Pourquier P, Rothwell DG, Inuzuka M, Weinstein JN, Ueda T, Appella E, Hickson ID, Pommier Y (2003) Human apurinic/apyrimidinic endonuclease (Ape1) and its N-terminal truncated form (AN34) are involved in DNA fragmentation during apoptosis. J Biol Chem 278:37768–37776

    Article  PubMed  CAS  Google Scholar 

  82. Zaky A, Busso C, Izumi T, Chattopadhyay R, Bassiouny A, Mitra S, Bhakat KK (2008) Regulation of the human AP-endonuclease (APE1/Ref-1) expression by the tumor suppressor p53 in response to DNA damage. Nucleic Acids Res 36:1555–1566

    Article  PubMed  CAS  Google Scholar 

  83. Heo JY, Jing K, Song KS, Seo KS, Park JH, Kim JS, Jung YJ, Hur GM, Jo DY, Kweon GR, Yoon WH, Lim K, Hwang BD, Jeon BH, Park JI (2009) Downregulation of APE1/Ref-1 is involved in the senescence of mesenchymal stem cells. Stem Cells 27:1455–1462

    Article  PubMed  CAS  Google Scholar 

  84. Robson CN, Hochhauser D, Craig R, Rack K, Buckle VJ, Hickson ID (1992) Structure of the human DNA repair gene HAP1 and its localisation to chromosome 14q 11.2–12. Nucleic Acids Res 20:4417–4421

    Article  PubMed  CAS  Google Scholar 

  85. Harrison L, Ascione G, Menninger JC, Ward DC, Demple B (1992) Human apurinic endonuclease gene (APE): structure and genomic mapping (chromosome 14q11.2–12). Hum Mol Genet 1:677–680

    Article  PubMed  CAS  Google Scholar 

  86. Konecki DS, Wang Y, Trefz FK, Lichter-Konecki U, Woo SL (1992) Structural characterization of the 5′ regions of the human phenylalanine hydroxylase gene. Biochemistry 31:8363–8368

    Article  PubMed  CAS  Google Scholar 

  87. Harrison L, Ascione AG, Wilson DM III, Demple B (1995) Characterization of the promoter region of the human apurinic endonuclease gene (APE). J Biol Chem 270:5556–5564

    Article  PubMed  CAS  Google Scholar 

  88. Rivkees SA, Kelley MR (1994) Expression of a multifunctional DNA repair enzyme gene, apurinic/apyrimidinic endonuclease (APE; Ref-1) in the suprachiasmatic, supraoptic and paraventricular nuclei. Brain Res 666:137–142

    Article  PubMed  CAS  Google Scholar 

  89. Fung H, Bennett RA, Demple B (2001) Key role of a downstream specificity protein 1 site in cell cycle-regulated transcription of the AP endonuclease gene APE1/APEX in NIH3T3 cells. J Biol Chem 276:42011–42017

    Article  PubMed  CAS  Google Scholar 

  90. Asai T, Kambe F, Kikumori T, Seo H (1997) Increase in Ref-1 mRNA and protein by thyrotropin in rat thyroid FRTL-5 cells. Biochem Biophys Res Commun 236:71–74

    Article  PubMed  CAS  Google Scholar 

  91. Grosch S, Fritz G, Kaina B (1998) Apurinic endonuclease (Ref-1) is induced in mammalian cells by oxidative stress and involved in clastogenic adaptation. Cancer Res 58:4410–4416

    PubMed  CAS  Google Scholar 

  92. Tell G, Pellizzari L, Pucillo C, Puglisi F, Cesselli D, Kelley MR, Di Loreto C, Damante G (2000) TSH controls Ref-1 nuclear translocation in thyroid cells. J Mol Endocrinol 24:383–390

    Article  PubMed  CAS  Google Scholar 

  93. Grosch S, Kaina B (1999) Transcriptional activation of apurinic/apyrimidinic endonuclease (Ape, Ref-1) by oxidative stress requires CREB. Biochem Biophys Res Commun 261:859–863

    Article  PubMed  CAS  Google Scholar 

  94. Pines A, Bivi N, Romanello M, Damante G, Kelley MR, Adamson ED, D’Andrea P, Quadrifoglio F, Moro L, Tell G (2005) Cross-regulation between Egr-1 and APE/Ref-1 during early response to oxidative stress in the human osteoblastic HOBIT cell line: evidence for an autoregulatory loop. Free Radic Res 39:269–281

    Article  PubMed  CAS  Google Scholar 

  95. Yoshida A, Pourquier P, Pommier Y (1998) Purification and characterization of a Mg2+-dependent endonuclease (AN34) from etoposide-treated human leukemia HL-60 cells undergoing apoptosis. Cancer Res 58:2576–2582

    PubMed  CAS  Google Scholar 

  96. Bots M, Medema JP (2006) Granzymes at a glance. J Cell Sci 119:5011–5014

    Article  PubMed  CAS  Google Scholar 

  97. Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS, Demple B, Perrino FW, Lieberman J (2006) The exonuclease TREX1 is in the SET complex and acts in concert with NM23–H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell 23:133–142

    Article  PubMed  CAS  Google Scholar 

  98. Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J (2003) Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol 4:145–153

    Article  PubMed  CAS  Google Scholar 

  99. Yan N, Cherepanov P, Daigle JE, Engelman A, Lieberman J (2009) The SET complex acts as a barrier to autointegration of HIV-1. PLoS Pathog 5:e1000327

    Article  PubMed  CAS  Google Scholar 

  100. 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 33:3303–3312

    Article  PubMed  CAS  Google Scholar 

  101. Tell G, Crivellato E, Pines A, Paron I, Pucillo C, Manzini G, Bandiera A, Kelley MR, Di Loreto C, Damante G (2001) Mitochondrial localization of APE/Ref-1 in thyroid cells. Mutat Res 485:143–152

    PubMed  CAS  Google Scholar 

  102. Li M, Zhong Z, Zhu J, Xiang D, Dai N, Cao X, Qing Y, Yang Z, Xie J, Li Z, Baugh L, Wang G, Wang D (2010) Identification and characterization of mitochondrial targeting sequence of human apurinic/apyrimidinic endonuclease 1. J Biol Chem 285:14871–14881

    Google Scholar 

  103. Nunez E, Fu XD, Rosenfeld MG (2009) Nuclear organization in the 3D space of the nucleus—cause or consequence? Curr Opin Genet Dev 19:424–436

    Article  PubMed  CAS  Google Scholar 

  104. Stein GS, van Wijnen AJ, Stein JL, Lian JB, Montecino M, Zaidi K, Javed A (2000) Subnuclear organization and trafficking of regulatory proteins: implications for biological control and cancer. J Cell Biochem Suppl Suppl 35:84–92

    Article  PubMed  CAS  Google Scholar 

  105. Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M (2005) Nucleolar proteome dynamics. Nature 433:77–83

    Article  PubMed  CAS  Google Scholar 

  106. Leung AK, Trinkle-Mulcahy L, Lam YW, Andersen JS, Mann M, Lamond AI (2006) NOPdb: nucleolar proteome database. Nucleic Acids Res 34:D218–D220

    Article  PubMed  CAS  Google Scholar 

  107. 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 35:2522–2532

    Article  PubMed  CAS  Google Scholar 

  108. Pinz KG, Bogenhagen DF (1998) Efficient repair of abasic sites in DNA by mitochondrial enzymes. Mol Cell Biol 18:1257–1265

    PubMed  CAS  Google Scholar 

  109. Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, Spitz DR, Goswami PC, Yodoi J, Gius D (2000) Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res 60:6688–6695

    PubMed  CAS  Google Scholar 

  110. Mitra S, Izumi T, Boldogh I, Bhakat KK, Chattopadhyay R, Szczesny B (2007) Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein. DNA Repair (Amst) 6:461–469

    Article  CAS  Google Scholar 

  111. Seo YR, Kelley MR, Smith ML (2002) Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci USA 99:14548–14553

    Article  PubMed  CAS  Google Scholar 

  112. Hanson S, Kim E, Deppert W (2005) Redox factor 1 (Ref-1) enhances specific DNA binding of p53 by promoting p53 tetramerization. Oncogene 24:1641–1647

    Article  PubMed  CAS  Google Scholar 

  113. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377:552–557

    Article  PubMed  CAS  Google Scholar 

  114. Okamoto K, Prives C (1999) A role of cyclin G in the process of apoptosis. Oncogene 18:4606–4615

    Article  PubMed  CAS  Google Scholar 

  115. Bernstein C, Bernstein H, Payne CM, Garewal H (2002) DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 511:145–178

    Article  PubMed  CAS  Google Scholar 

  116. Di Maso V, Avellini C, Croce LS, Rosso N, Quadrifoglio F, Cesaratto L, Codarin E, Bedogni G, Beltrami CA, Tell G, Tiribelli C (2007) Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma: possible prognostic significance. Mol Med 13:89–96

    Article  PubMed  CAS  Google Scholar 

  117. Duguid JR, Eble JN, Wilson TM, Kelley MR (1995) Differential cellular and subcellular expression of the human multifunctional apurinic/apyrimidinic endonuclease (APE/ref-1) DNA repair enzyme. Cancer Res 55:6097–6102

    PubMed  CAS  Google Scholar 

  118. 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 11:7405–7414

    Article  PubMed  CAS  Google Scholar 

  119. Luo M, He H, Kelley MR, Georgiadis MM. Redox regulation of DNA repair: implications for human health and cancer therapeutic development (2010) Antioxid Redox Signal 12:1247–1269

  120. Messina M, Kucuk O, Lampe JW (2006) An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J AOAC Int 89:1121–1134

    PubMed  CAS  Google Scholar 

  121. Yang S, Irani K, Heffron SE, Jurnak F, Meyskens FL Jr (2005) Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor. Mol Cancer Ther 4:1923–1935

    Article  PubMed  CAS  Google Scholar 

  122. 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 38:832–845

    Google Scholar 

  123. Shimizu N, Sugimoto K, Tang J, Nishi T, Sato I, Hiramoto M, Aizawa S, Hatakeyama M, Ohba R, Hatori H, Yoshikawa T, Suzuki F, Oomori A, Tanaka H, Kawaguchi H, Watanabe H, Handa H (2000) High-performance affinity beads for identifying drug receptors. Nat Biotechnol 18:877–881

    Article  PubMed  CAS  Google Scholar 

  124. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8:193–204

    Article  PubMed  CAS  Google Scholar 

  125. Bennett RA, Wilson DM III, 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 94:7166–7169

    Article  PubMed  CAS  Google Scholar 

  126. Dianova II, Bohr VA, Dianov GL (2001) Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair. Biochemistry 40:12639–12644

    Article  PubMed  CAS  Google Scholar 

  127. Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL (2001) Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. J Biol Chem 276:5547–5555

    Article  PubMed  CAS  Google Scholar 

  128. 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 20:6530–6539

    Article  PubMed  CAS  Google Scholar 

  129. Busso CS, Iwakuma T, Izumi T (2009) Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene 28:1616–1625

    Article  PubMed  CAS  Google Scholar 

  130. Fritz G, Grosch S, Tomicic M, Kaina B (2003) APE/Ref-1 and the mammalian response to genotoxic stress. Toxicology 193:67–78

    Article  PubMed  CAS  Google Scholar 

  131. Hegde V, Wang M, Deutsch WA (2004) Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGG1. Biochemistry 43:14211–14217

    Article  PubMed  CAS  Google Scholar 

  132. Sidorenko VS, Nevinsky GA, Zharkov DO (2007) Mechanism of interaction between human 8-oxoguanine-DNA glycosylase and AP endonuclease. DNA Repair (Amst) 6:317–328

    Article  CAS  Google Scholar 

  133. Gembka A, Toueille M, Smirnova E, Poltz R, Ferrari E, Villani G, Hubscher U (2007) The checkpoint clamp, Rad9-Rad1-Hus1 complex, preferentially stimulates the activity of apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta in long patch base excision repair. Nucleic Acids Res 35:2596–2608

    Article  PubMed  CAS  Google Scholar 

  134. Curtis CD, Thorngren DL, Ziegler YS, Sarkeshik A, Yates JR, Nardulli AM (2009) Apurinic/apyrimidinic endonuclease 1 alters estrogen receptor activity and estrogen-responsive gene expression. Mol Endocrinol 23:1346–1359

    Article  PubMed  CAS  Google Scholar 

  135. Huang E, Qu D, Zhang Y, Venderova K, Haque ME, Rousseaux MW, Slack RS, Woulfe JM, Park DS (2010) The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death. Nat Cell Biol 12:563–571

    Article  PubMed  CAS  Google Scholar 

  136. Izumi T, Mitra S (1998) Deletion analysis of human AP-endonuclease: minimum sequence required for the endonuclease activity. Carcinogenesis 19:525–527

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Mark R. Kelley for helpful discussions. This work was supported by grants from: MIUR (FIRB RBRN07BMCT_008 and PRIN 2008CCPKRP_003) and from MAE (Joint Mobility Projects Program 2008–2010) to G.T.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences and Technologies, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy

    Gianluca Tell, Damiano Fantini & Franco Quadrifoglio

Authors
  1. Gianluca Tell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Damiano Fantini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franco Quadrifoglio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gianluca Tell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tell, G., Fantini, D. & Quadrifoglio, F. Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment. Cell. Mol. Life Sci. 67, 3589–3608 (2010). https://doi.org/10.1007/s00018-010-0486-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0486-4

Keywords

Search

Navigation