title: Effect of 8-oxoguanine on DNA structure and deformability.
abstract: 8-Oxoguanine (oxoG) is an abundant product of oxidative DNA damage. It is removed by repair glycosylases, but exactly how the enzymes recognize oxoG in the large surplus of undamaged bases is not fully understood. The lesion may induce changes in the properties of naked DNA that facilitate the recognition. In this work, we assess the effect of oxoG on DNA structure and mechanical deformability. We performed extensive unrestrained, atomic resolution molecular dynamics simulations to parametrize a nonlocal, rigid base mechanical model of DNA. Our data indicate that oxoG induces unwinding of the base pair step at the 5'-side of the lesion. This brings the damaged DNA closer to its conformation in the initial complex with bacterial glycosylase MutM. The untwisting is partially caused by different BII substate populations and is further enhanced by the base-sugar repulsion within oxoG. On the other hand, our analysis shows that damaged and undamaged DNA have very similar harmonic stiffness. These results suggest an indirect readout component of the MutM-DNA initial complex formation. They also help one to understand the effect of oxoG on the formation of nucleosomes and looped gene regulatory complexes.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Flemingovo náměstı́ 2, 166 10, Praha 6, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Dršata
authors.forename: Mahmut
authors.initials: M
authors.lastname: Kara
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
authors.forename: Filip
authors.initials: F
authors.lastname: Lankaš
mesh_terms: D000465:Algorithms; D001426:Bacterial Proteins / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D055595:Mechanical Phenomena; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009690:Nucleic Acid Conformation
chemical_list: D001426:Bacterial Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D045647:DNA Glycosylases