Abstract
5,6-Dihydroxy-5,6-dihydrothymine (thymine glycol) and 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG) are major DNA damage lesions produced by endogenous oxidative stress, as well as inflicted by carcinogens and ionizing radiation. The processing of Tg:G mismatch and 8-oxodG in close proximity of each other in a bistranded clustered environment in DNA oligomer duplexes as well as in a nucleosome core particle (NCP) model are reported here. The processing of the lesions was evaluated by purified enzyme cocktails of hNTH1 and hOGG1 as well as with a HeLa cell extract. Interestingly, the yield of double-strand breaks (DSBs) resulting from the processing of the bistranded lesions are appreciably lower when the DNA is treated with the HeLa cell extract compared with the relevant purified enzyme cocktail in both models. Clustered bistranded lesions become more repair refractive when reconstituted as an NCP. This indicates a complex interplay between the repair enzymes that influence the processing of the bistranded cluster damage positively to avoid the formation of DSBs under cellular conditions. In addition to position and orientation of the lesions, the type of the lesions in the cluster environment in DNA along with the relative abundance of the lesion-specific enzymes in the cells strongly prevents the processing of the oxidized nucleobases.
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References
Breslauer KJ 1994 Extracting thermodynamic data from equilibrium melting curves for oligonucleotide order-disorder transitions methods. Mol. Biol. 26 347–372
Brown KL, Basu AK and Stone MP 2009 The cis-(5R,6S)-thymine glycol lesion occupies the wobble position when mismatched with deoxyguanosine in DNA. Biochemistry 48 9722–9733
Cathcart R, Schwiers E, Saul RL and Ames BN 1984 Thymine glycol and thymidine glycol in human and rat urine: a possible assay for oxidative DNA damage. Proc. Natl. Acad. Sci. 81 5633–5637
Chaudhry MA 2007 Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases. Cancer Cell Interact. 7:15
Cole HA, Tabor-Godwin JM and Hayes JJ 2010 Uracil DNA glycosylase activity on nucleosomal DNA depends on rotational orientation of targets. J. Biol. Chem. 285 2876–2885.
Crenshaw CM, Wade JE, Arthanari H, Frueh D, Lane BF and Núñez ME 2011 Hidden in plain sight: subtle effects of the 8-oxoguanine lesion on the structure, dynamics, and thermodynamics of a 15 base-pair oligodeoxynucleotide duplex. Biochemistry 50 8463–8477
Dolinnaya NG, Kubareva EA, Romanova EA, Trikin RM and Oretskaya TS 2013 Thymidine glycol: the effect on DNA molecular structure and enzymatic processing. Biochimie 95 134–147
Eccles LJ, Menoni H, Angelov D, Lomax ME and O’Neill P 2015 Efficient cleavage of single and clustered AP site lesions within mono-nucleosome templates by CHO-K1 nuclear extract contrasts with retardation of incision by purified APE1. DNA Repair 35 27–36
Gontijo AM, Green CM and Almouzni G 2003 Repairing DNA damage in chromatin. Biochimie 85 1133–1147
Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G, Zhu H, Chang Q, Gao Y, Ming G and Song H 2014 Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat. Neurosci. 17 215–222
Hinz JM 2014 Impact of abasic site orientation within nucleosomes on human APE1 endonuclease activity. Mutat. Res. 766–767 19–24
Juo S, Boorstein RJ and Teebor GW 1995 Oxidative damage to 5-methylcytosine in DNA. Nucleic Acid Res. 23 3239–3243
Katafuchi A, Nakano T, Masaoka A, Terato H, Iwai S, Hanaoka F and Ida H 2004 Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions. J. Biol. Chem. 279 14464–14471
Kung HC and Bolton PH 1997 Structure of a duplex DNA containing a thymine glycol residue in solution. J. Biol. Chem. 272 9227–9236
Kypr J, Kejnovská I, Renčiuk D and Vorlíčková M 2009 Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res. 37 1713–1725
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B and Ecker JR 2009 Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462 315–322
Loft S, Fischer-Nielsen A, Jeding IB, Vistisen K and Poulsen HE 1993 8-Hydroxydeoxyguanosine as a urinary biomarker of oxidative DNA damage. J. Toxicol. Environ. Health 40 391–404
Marenstein DR, Chan MK, Altamirano A, Basu AK, Boorstein RJ, Cunningham RP and Teebor GW 2003 Substrate specificity of human endonuclease III (hNTH1). Effect of human APE1 on hNTH1 activity. J. Biol. Chem. 278 9005–9012
McGhee JD, Felsenfeld G and Eisenberg H 1980 Nucleosome structure and conformational changes. Biophys. J. 32 261–270
Mei N, Kunugita N, Hirano T and Kasai H 2002 Acute arsenite-induced 8-hydroxyguanine is associated with inhibition of repair activity in cultured human cells. Biochem. Biophys. Res. Commun. 297 924–930
Menoni H, Shukla MS, Gerson V, Dimitrov S and Angelov D 2012 Base excision repair of 8-oxoG in dinucleosomes. Nucleic Acids Res. 40 692–700
Minetti CA, Remeta DP, Iden CR, Johnson F, Grollman AP and Breslauer KJ 2015 Impact of thymine glycol damage on DNA duplex energetics: correlations with lesion-induced biochemical and structural consequences. Biopolymers 103 491–508
Ocampo-Hafalla MT, Altamirano A, Basu AK, Chan MK, Ocampo JE, Cummings AJ, Boorstein RJ, Cunningham RP and Teebor GW 2006 Repair of thymine glycol by hNTH1and hNEIL1 is modulated by base pairing and cis trans epimerization. DNA Repair 5 444–454
Odell ID, Barbour JE, Murphy DL, Della-Maria JA, Sweasy JB, Tomkinson AE, Wallace SS and Pederson DS 2011 Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair. Mol. Cell Biol. 31 4623–4632
Odell ID, Newick K, Heintz NH, Wallace SS and Pederson DS 2010 Non-specific DNA binding interferes with the efficient excision of oxidative lesions from chromatin by the human DNA glycosylase, NEIL1. DNA Repair (Amsterdam) 9 134–143
Prasad A, Wallace SS and Pederson DS 2007 Initiation of base excision repair of oxidative lesions in nucleosomes by the human, bifunctional DNA glycosylase NTH1. Mol. Cell Biol. 27 8442–8453
Rosenquist TA, Zharkov DO and Grollman AP 1997 Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc. Natl. Acad. Sci. 94 7429–7434
Singh V and Das P 2013 Condensation of DNA – a putative obstruction for repair process in abasic clustered DNA damage. DNA Repair 12 450–457
Singh V, Kumari B and Das P 2015 Repair efficiency of clustered abasic sites by APE1 in nucleosome core particles is sequence and position dependent. RSC Adv. 5 23691–23698
Suzuki MM and Bird A 2008 DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9 465–476
Acknowledgements
This work was supported by a grant from the Department of Science and Technology, Govt. of India (SERB, Grant No. SR/FT/LS-36/2010). The authors are thankful to IIT Patna and NIPER Hajipur for infrastructure and experimental facilities.
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Kumari, B., Sinha, K.K. & Das, P. Complex interplay of lesion-specific DNA repair enzyme on bistranded clustered DNA damage harboring Tg:G mismatch in nucleosome core particles. J Biosci 43, 575–583 (2018). https://doi.org/10.1007/s12038-018-9786-x
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DOI: https://doi.org/10.1007/s12038-018-9786-x