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H2O2-induced higher order chromatin degradation: A novel mechanism of oxidative genotoxicity

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Abstract

The genotoxicity of reactive oxygen species (ROS) is well established. The underlying mechanism involves oxidation of DNA by ROS. However, we have recently shown that hydrogen peroxide (H2O2), the major mediator of oxidative stress, can also cause genomic damage indirectly. Thus, H2O2 at pathologically relevant concentrations rapidly induces higher order chromatin degradation (HOCD), i.e. enzymatic excision of chromatin loops and their oligomers at matrix-attachment regions. The activation of endonuclease that catalyzes HOCD is a signalling event triggered specifically by H2O2. The activation is not mediated by an influx of calcium ions, but resting concentrations of intracellular calcium ions are required for the maintenance of the endonuclease in an active form. Although H2O2-induced HOCD can efficiently dismantle the genome leading to cell death, under sublethal oxidative stress conditions H2O2-induced HOCD may be the major source of somatic mutations.

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Abbreviations

HOCD:

Higher order chromatin degradation

MAR:

matrix attachment region

References

  • Bai H. and Konat G. W. 2002 Hydrogen peroxide mediates higher order chromatin digestion;Neurochem. Int. 42 123–129

    Article  Google Scholar 

  • Baynes J. W. 2000 From life to death the struggle between chemistry and biology during aging: the Maillard reaction as an amplifier of genomic damage;Biogerontology 1 235–246

    Article  CAS  Google Scholar 

  • Beere H M, Chresta C M, Alejo-Herberg A, Skladanowski A, Dive C, Larsen A K and Hickman J A 1995 Investigation of the mechanism of higher order chromatin fragmentation observed in drug-induced apoptosis;Mol. Pharmacol. 47 986–996

    CAS  PubMed  Google Scholar 

  • Boles T C and Hogan M E 1987 DNA structure equilibria in the human c-myc gene;Biochemistry 26 367–376

    Article  CAS  Google Scholar 

  • Bredesen D E 1995 Neural apoptosis;Ann. Neurol. 38 839–851

    Article  CAS  Google Scholar 

  • Breen A P and Murphy J A 1995 Reactions of oxyl radicals with DNA;Free Rad. Biol. Med. 18 1033–1077

    Article  CAS  Google Scholar 

  • Brown D G, Sun X M and Cohen G M 1993 Dexamethasoneinduced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation;J. Biol. Chem. 268 3037–3039

    CAS  PubMed  Google Scholar 

  • Cohen G M, Sun X M, Fearnhea H, MacFarlane M, Brown D G, Snowden R T and Dinsdale D 1994 Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes;J. Immunol. 153 507–516

    CAS  PubMed  Google Scholar 

  • Cutler R G 1992 Genetic stability and oxidative stress: common mechanisms in aging and cancer; inFree radicals and aging (eds) I Emerit and B Chance (Basel: Birkhauser Verlag) pp 31–46

    Chapter  Google Scholar 

  • Dominguez I, Daza P, Natarajan A T and Cortez F 1998 A high yield of translocations parallels the high yield of sister chromatin exchanges in the CHO mutant EM9;Mutat. Res. 398 67–73

    Article  CAS  Google Scholar 

  • Halliwell B and Aruoma O I 1991 DNA damage by oxygenderived species. Its mechanism and measurment in mammal ian systems;FEBS Lett. 281 9–19

    Article  CAS  Google Scholar 

  • Halliwell B and Gutteridge J M 1989Free radicals in biology and medicine (Oxford: Clarendon Press)

    Google Scholar 

  • Henle E S and Linn S 1997 Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide;J. Biol. Chem. 272 19095–19098

    Article  CAS  Google Scholar 

  • Hyslop P A, Zhang Z, Pearson D V and Phebus L A 1995 Measurement of striatal H2O2 by microdialysis following global forebrain ischemia and reperfusion in the rat: correlation with the cytotoxic potential of H2O2 in vitro;Brain Res. 671 181–186

    Article  CAS  Google Scholar 

  • Khanna K K and Jackson S P 2001 DNA double-strand breaks: signaling, repair and the cancer connection;Nature Genet. 27 247–254

    Article  CAS  Google Scholar 

  • Klaunig J E, Xu Y, Isenberg J S, Bachowski S, Kolaja K L, Jiang J, Stevenson D E and Walborg E F Jr 1998 The role of oxidative stress in chemical carcinogenesis;Environ. Health Perspect (Suppl 1) 106 289–295

    CAS  Google Scholar 

  • Konat G W, Mouzannar R and Bai H 2001 Higher order chromatin degradation in glial cells: The role of calcium;Neurochem. Int. 39 179–186

    Article  CAS  Google Scholar 

  • Kovacic P and Jacintho J D 2001 Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer;Curr. Med. Chem. 8 773–796

    Article  CAS  Google Scholar 

  • Kroemer G, Zamzami N and Susin S A 1997 Mitochondrial control of apoptosis;Immunol. Today 18 43–51

    Article  Google Scholar 

  • Kuzminov A 2001 Single strand interruptions in replicating chromosomes cause double strand breaks;Proc. Natl. Acad. Sci. USA 98 8241–8246

    Article  CAS  Google Scholar 

  • Lagarkova M A, Iarovaia O V and Razin S V 1995 Large scale fragmentation of mammalian DNA in the course of apoptosis procedes via excision of chromosomal DNA loops and their oligomers;J. Biol. Chem. 270 20239–20245

    Article  CAS  Google Scholar 

  • Li Y, Zhu H, Stansbury K H and Trush M A 1997 Role of reactive oxygen species in multistage carcinogenesis; inOxygen radicals and the disease process (eds) C.E. Thomas and H.Kalyanaram μmsterdam; Harwood Academic Publishers) pp 237–277

    Google Scholar 

  • Lin Y and Waldman A S 2001 Capture of DNA sequences at double-strand breaks in mammalian chromosomes;Genetics 158 1665–1674

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loft S and Poulsen H E 1996 Cancer risk and oxidative DNA damage in man;J. Mol. Med. 74 297–312

    Article  CAS  Google Scholar 

  • Mouzannar R, Miric S J, Wiggins R C and Konat G W 2001 Hydrogen peroxide induces rapid digestion of oligodendrocyte chromatin into high molecular weight fragments;Neurochem. Int. 38 9–15

    Article  CAS  Google Scholar 

  • Nickol J M and Felsenfeld G 1983 DNA conformation at the 5′ end of the chicken adult beta-globin gene;Cell 35 467–477

    Article  CAS  Google Scholar 

  • Oberhammer F, Wilson J W, Dive C, Morris I D, Hickman J A, Wakeling A E, Walker P R and Sikorska M 1993 Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation;EMBO J. 12 3679–3684

    Article  CAS  Google Scholar 

  • Poulsen H E, Prieme H and Loft S 1998 Role of oxidative DNA damage in cancer initiation and promotion;Eur. J. Cancer Prev. 7 9–16

    CAS  PubMed  Google Scholar 

  • Quillet-Mary A, Jaffrezou J-P, Mansat V, Brodier C, Naval J and Laurent G 1995 Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis;J. Biol. Chem. 272 21388–21395

    Article  Google Scholar 

  • Reynolds W F and Gottesfeld J M 1985 Torsional stress induces an S1 nuclease-hypersensitive site within the promoter of theXenopus laevis oocyte-type 5S RNA gene;Proc. Natl. Acad. Sci. USA 82 4018–4022

    Article  CAS  Google Scholar 

  • Richardson C and Jasin M 2000 Frequent chromosomal translocations induced by DNA double-strand breaks;Nature (itLondon) 405 697–700

    Article  CAS  Google Scholar 

  • Ruiz-Carrillo A 1984 The histone H5 gene is flanked by S1 hypersensitive structures;Nucleic Acid Res. 12 6473–6492

    Article  CAS  Google Scholar 

  • Sun X M, Snowden R T, Dinsdale D, Ormerod M G and Cohen G M 1993 Changes in nuclear chromatin precede internu cleosomal DNA cleavage in the induction of apoptosis by etoposide;Biochem. Pharmacol. 2 187–195

    Google Scholar 

  • Thompson L H, Brookman K W, Dillehay L E, Carano A V, Mazrimas J A, Mooney C L and Minkler J L 1982 A CHOcell strain having hypersensitivity to mutagens, a defect in strand-break repair, and an extraordinary baseline of frequency of sister chromatid exchange;Mutat. Res. 95 427–440

    Article  CAS  Google Scholar 

  • Turker M S, Gage B M, Rose J A, Elroy D, Ponomareva O N, Stambrook P J and Tischfield J A 1999 A novel signature mutation for oxidative damage resembles a mutational pattern found commonly innhuman cancers;Cancer Res. 59 1837–1839

    CAS  PubMed  Google Scholar 

  • Um H D, Orenstein J M and Wahl S M 1996 Fas mediates apotosis in human monocytes by a reactive oxygen intermediate dependent pathway;J. Immunol. 156 3469–3477

    CAS  PubMed  Google Scholar 

  • Veld C W O H, Jansen J, Zdzienicka M Z, Vrieling H and van Zeeland A A 1998 Methyl methane sulfonate induced hprt mutation spectra in the Chinese hamster cell line CH09 and its xrcc1-deficient derivative EM-C11;Mutat. Res-Fundam. Mol. Mech. Mutagenes 398 83–92

    Article  Google Scholar 

  • Walker P R, LeBlanc J and Sikorska M 1997 Evidence that DNA fragmentation in apoptosis is initiated and propa gated by single-strand breaks;Cell Death Differ. 4 506–515

    Article  CAS  Google Scholar 

  • Wang J N C and Hogan M 1985 An equilibrium between distorted and undistorted DNA in the adult chicken beta Aglobin gene;J. Biol. Chem. 260 8194–8202

    CAS  PubMed  Google Scholar 

  • Winegar R A, Lutze L H, Rufer J T and Morgan W F 1992 Spectrum of mutations produced by specific types of restric tion enzyme-induced double-strand breaks;Mutagenesis 7 439–445

    Article  CAS  Google Scholar 

  • Yeldandi A V, Rao M S and Reddy J K 2000 Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis;Mutat. Res. 448 159–177

    Article  CAS  Google Scholar 

  • Zhivotovsky B, Cederall B, Jiang S, Nicotera P and Orrenius S 1994 Involvement of Ca2+ in the formation of high molecular weight DNA fragments in thymocyte apoptosis;Biophys. Biochem. Res. Commun. 202 120–127

    Article  CAS  Google Scholar 

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  1. Department of Neurobiology and Anatomy, West Virginia University School of Medicine, 4052 HSN, PO Box 9128, 26506-9128, Morgantown, WV, USA

    Gregory W. Konat

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Correspondence to Gregory W. Konat.

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Konat, G.W. H2O2-induced higher order chromatin degradation: A novel mechanism of oxidative genotoxicity. J. Biosci. 28, 57–60 (2003). https://doi.org/10.1007/BF02970132

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