Oxidatively-generated interstrand cross-links rank among the most deleterious DNA lesions. They originate from abasic sites, whose aldehyde group can form a covalent adduct after condensation with the exocyclic amino group of purines, sometimes with remarkably high yields. We use explicit solvent molecular dynamics simulations to unravel the structures and mechanical properties of two DNA sequences containing an interstrand cross-link. Our simulations palliate the absence of experimental structural and stiffness information for such DNA lesions and provide an unprecedented insight into the DNA embedding of lesions that represent a major challenge for DNA replication, transcription and gene regulation by preventing strand separation. Our results based on quantum chemical calculations also suggest that the embedding of the ICL within the duplex can tune the reaction profile, and hence can be responsible for the high difference in yields of formation.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo nám 2 166 10 Praha 6 Czech Republic

Laboratory of Informatics and Chemistry University of Chemistry and Technology Prague Technická 5 166 28 Praha 6 Czech Republic

Univ Lyon CNRS Université Claude Bernard Lyon 1 Ens de Lyon Institut des Sciences Analytiques UMR 5280 5 rue de la Doua F 69100 Villeurbanne France

Univ Lyon Ens de Lyon CNRS UMR 5182 Université Claude Bernard Lyon 1 Laboratoire de Chimie F69342 Lyon France

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Cooke M.S., Evans M.D., Dizdaroglu M., Lunec J.. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003; 17:1195–1214. PubMed

Box H.C., Budzinski E.E., Dawidzik J.B., Gobey J.S., Freund H.G.. Free radical-induced tandem base damage in DNA oligomers. Free Rad. Biol. Med. 1997; 23:1021–1030. PubMed

Dutta S., Chowdhury G., Gates K.S.. Interstrand cross-links generated by abasic sites in duplex DNA. J. Am. Chem. Soc. 2007; 129:1852–1853. PubMed PMC

Ding H., Majumdar A., Tolman J.R., Greenberg M.M.. Multinuclear NMR and kinetic analysis of DNA interstrand cross-link formation. J. Am. Chem. Soc. 2008; 130:17981–17987. PubMed PMC

Wang J., Cao H., You C., Yuan B., Bahde R., Gupta S., Nishigori C., Niedernhofer L.J., Brooks P.J., Wang Y.. Endogenous formation and repair of oxidatively induced G[8-5m]T intrastrand cross-link lesion. Nucleic Acids Res. 2012; 40:7368–7374. PubMed PMC

Johnson K.M., Price N.E., Wang J., Fekry M.I., Dutta S., Seiner D.R., Wang Y., Gates K.S.. On the formation and properties of interstrand DNA–DNA cross-links forged by reaction of an abasic site with the opposing guanine residue of 5’-CAp sequences in duplex DNA. J. Am. Chem. Soc. 2013; 135:1015–1025. PubMed PMC

Price N.E., Johnson K.M., Wang J., Fekry M.I., Wang Y., Gates K.S.. Interstrand DNA–DNA cross-link formation between adenine residues and abasic sites in duplex DNA. J. Am. Chem. Soc. 2014; 136:3483–3490. PubMed PMC

Price N.E., Catalano M.J., Liu S., Wang Y., Gates K.S.. Chemical and structural characterization of interstrand cross-links formed between abasic sites and adenine residues in duplex DNA. Nucleic Acids Res. 2015; 43:3434–3441. PubMed PMC

Catalano M.J., Liu S., Andersen N., Yang Z., Johnson K.M., Price N.E., Wang Y., Gates K.S.. Chemical structure and properties of interstrand cross-links formed by reaction of guanine residues with abasic sites in duplex DNA. J. Am. Chem. Soc. 2015; 137:3933–3945. PubMed PMC

Yang Z., Price N.E., Johnson K.M., Gates K.S.. Characterization of interstrand DNA–DNA cross-links derived from abasic sites using bacteriophage ϕ29 DNA polymerase. Biochemistry. 2015; 54:4259–4266. PubMed PMC

Zhang X., Price N.E., Fang X., Yang Z., Gu L.-Q., Gates K.S.. Characterization of interstrand DNA–DNA cross-links using the α-hemolysin protein nanopore. ACS Nano. 2015; 9:11812–11819. PubMed PMC

Sczepanski J.T., Jacobs A.C., Majumdar A., Greenberg M.M.. Scope and mechanism of interstrand cross-link formation by the C4’-oxidized abasic site. J. Am. Chem. Soc. 2009; 131:11132–11139. PubMed PMC

Regulus P., Duroux B., Bayle P.-A., Favier A., Cadet J., Ravanat J.-L.. Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion. Proc. Natl. Acad. Sci. U.S.A. 2007; 104:14032–14037. PubMed PMC

Noll D.M., Mason T.M., Miller P.S.. Formation and repair of interstrand cross-Links in DNA. Chem. Rev. 2006; 106:277–301. PubMed PMC

Ghosh S., Greenberg M.M.. Correlation of thermal stability and structural distortion of DNA interstrand cross-links produced from oxidized abasic sites with their selective formation and repair. Biochemistry. 2015; 54:6274–6283. PubMed PMC

Kamiya H. Mutagenic potentials of damaged nucleic acids produced by reactive oxygen/nitrogen species: approaches using synthetic oligonucleotides and nucleotides: survey and summary. Nucleic Acids Res. 2003; 31:517–531. PubMed PMC

Catalano M.J., Ruddraraju V., Barnes C.L., Gates K.S.. Crystal structure of a nucleoside model for the interstrand cross-link formed by the reaction of 2’-deoxyguanosine and an abasic site in duplex DNA. Acta Cryst. 2016; E72:624–627. PubMed PMC

Hlavin E.M., Smeaton M.B., Miller P.S.. Initiation of DNA interstrand cross-link repair in mammalian cells. Environ. Mol. Mutagen. 2010; 51:604–624. PubMed PMC

Clauson C., Schärer O.D., Niedernhofer L.. Advances in understanding the complex mechanisms of DNA interstrand cross-link repair. Cold Spring Harb. Perspect. Biol. 2013; 5:a012732. PubMed PMC

Williams H.L., Gottesman M.E., Gautier J.. The differences between ICL repair during and outside of S phase. Trends Biochem. Sci. 2013; 38:386–393. PubMed PMC

Wilhelm M., Mukherjee A., Bouvier B., Zakrzewska K., Hynes J.T., Lavery R.. Multistep drug intercalation: molecular dynamics and free energy studies of the binding of daunomycin to DNA. J. Am. Chem. Soc. 2012; 134:8588–8596. PubMed

Dumont E., Monari A.. Benzophenone and DNA: Evidence for a double insertion mode and its spectral signature. J. Phys. Chem. Lett. 2013; 4:4119–4124.

Churchill C. D.M., Eriksson L.A., Wetmore S.D.. Formation mechanism and structure of a guanine–uracil DNA intrastrand cross-link. Chem. Res. Toxicol. 2011; 24:2189–2199. PubMed

Dumont E., Dršata T., Fonseca Guerra C., Lankaš F.. Insights into the structure of intrastrand cross-link DNA lesion-containing oligonucleotides: G[8–5m]T and G[8–5]C from molecular dynamics simulations. Biochemistry. 2015; 54:1259–1267. PubMed

Churchill C. D.M., Eriksson L.A., Wetmore S.D.. DNA Distortion Caused by Uracil-Containing Intrastrand Cross-Links. J. Phys. Chem. B. 2016; 120:1195–1204. PubMed

Case D.A., Darden T.A., Cheatham T.E. III, Simmerling C.L., Wang J., Duke R.E., Luo R., Walker R.C., Zhang W., Merz K.M. et al. . AMBER 12. 2012; San Francisco: University of California.

Ayadi L., Coulombeau C., Lavery R.. Abasic sites in duplex DNA: molecular modeling of sequence-dependent effects on conformation. Biophys. J. 1999; 77:3218–3226. PubMed PMC

Barsky D., Foloppe N., Ahmadia S., Wilson III D.M., MacKerell A.D. Jr. New insights into the structure of abasic DNA from molecular dynamics simulations. Nucleic Acids Res. 2000; 28:2613–2626. PubMed PMC

Chen J., Dupradeau F.-Y., Case D.A., Turner C.J., Stubbe J.. DNA oligonucleotides with A, T, G or C opposite an abasic site: structure and dynamics. Nucleic Acids Res. 2008; 36:253–262. PubMed PMC

Ivani I., Dans P.D., Noy A., Perez A., Faustino I., Hospital A., Walther J., Andrio P., Goñi R., Balaceanu A. et al. . Parmbsc1: a refined force-field for DNA simulations. Nat. Methods. 2016; 13:55–58. PubMed PMC

Galindo-Murillo R., Robertson J.C., Zgarbová M., Šponer J., Otyepka M., Jureačka P., Cheatham T.E.. Assessing the current state of amber force field modifications for DNA. J. Chem. Theory Comput. 2016; 12:4114–4127. PubMed PMC

Sviatenko L., Gorb L., Hovorun D., Leszczynski J.. Interaction of 2-Deoxyadenosine with cis-2-Butene-1,4-dial: Computational approach to analysis of multistep chemical reactions. J. Phys. Chem. A. 2012; 116:2333–2342. PubMed

Fonseca Guerra C., van der Wijst T., Poater J., Swart M., Bickelhaupt F.M.. Adenine versus guanine quartets in aqueous solution: dispersion-corrected DFT study on the differences in π-stacking and hydrogen-bonding behavior. Theor. Chem. Acc. 2010; 125:245–252.

Dupont C., Patel C., Dumont E.. Improved DFT description of intrastrand cross-link formation by inclusion of london dispersion corrections. J. Phys. Chem. B. 2011; 115:15138–15144. PubMed

Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Mennucci B., Petersson G. A. et al. . G.A.P. Gaussian∼09 Revision D.01. 2009; Wallingford: Gaussian Inc.

Lu X.-J., Olson W.K.. 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res. 2003; 31:5108–5121. PubMed PMC

Drsata T., Lankas F.. Theoretical models of DNA flexibility. WIREs Comput. Mol. Sci. 2013; 3:355–363.

Drsata T., Spackova N., Jurecka P., Zgarbova M., Sponer J., Lankas F.. Mechanical properties of symmetric and asymmetric DNA A-tracts: implications for looping and nucleosome positioning. Nucleic Acids Res. 2014; 42:7383–7394. PubMed PMC

Andricioaei I., Karplus M.. On the calculation of entropy from covariance matrices of the atomic fluctuations. J. Chem. Phys. 2001; 115:6289–6292.

Lankas F., Spackova N., Moakher M., Purevjav E., Sponer J.. A measure of bending in nucleic acids structures applied to A-tract DNA. Nucleic Acids Res. 2010; 38:3414–3422. PubMed PMC

Patel C., Garrec J., Dupont C., Dumont E.. What singles out the G[8-5]C intrastrand DNA cross-link? mechanistic and structural insights from quantum mechanics/molecular mechanics simulations. Biochemistry. 2013; 52:425–431. PubMed

Kim J.-K., Patel D., Choi B.-S.. Contrasting structural impacts induced by cis-syn cyclobutane dimer and (6-4) adduct in DNA duplex decamers: implication in mutagenesis and repair activity. Photochem. Photobiol. 1995; 62:44–50. PubMed

Noll D.M., Mason T.M., Miller P.S.. Formation and Repair of Interstrand Cross-Links in DNA. Chem. Rev. 2006; 106:277–301. PubMed PMC

Fridman A.S., Brabec V., Haroutiunian S.G., Wartell R.M., Lando D.Y.. Melting of cross-linked DNA V. Cross-linking effect caused by local stabilization of the double helix. J. Biomol. Struct. Dyn. 2003; 20:533–545. PubMed

Roychoudhury M., Sitlani A., Lapham J., Crothers D.M.. Global structure and mechanical properties of a 10-bp nucleosome positioning motif. Proc. Natl. Acad. Sci. U.S.A. 2000; 97:13608–13613. PubMed PMC

Catalano M.J., Liu S., Andersen N., Yang Z., Johnson K.M., Price N.E., Wang Y., Gates K.S.. Chemical structure and properties of interstrand cross-links formed by reaction of guanine residues with abasic sites in duplex DNA. J. Am. Chem. Soc. 2015; 137:3933–3945. PubMed PMC