Document Type
Article
Publication Date
4-2016
Publication Title
Biochemistry
Abstract
DNA is constantly under attack by oxidants, generating a variety of potentially mutagenic covalently modified species, including oxidized guanine base products. One such product is spiroiminodihydantoin (Sp), a chiral, propeller-shaped lesion that strongly destabilizes the DNA helix in its vicinity. Despite its unusual shape and thermodynamic effect on double-stranded DNA structure, DNA duplexes containing the Sp lesion form stable nucleosomes upon being incubated with histone octamers. Indeed, among six different combinations of lesion location and stereochemistry, only two duplexes display a diminished ability to form nucleosomes, and these only by ∼25%; the other four are statistically indistinguishable from the control. Nonetheless, kinetic factors also play a role: when the histone proteins have less time during assembly of the core particle to sample both lesion-containing and normal DNA strands, they are more likely to bind the Sp lesion DNA than during slower assembly processes that better approximate thermodynamic equilibrium. Using DNase I footprinting and molecular modeling, we discovered that the Sp lesion causes only a small perturbation (±1–2 bp) on the translational position of the DNA within the nucleosome. Each diastereomeric pair of lesions has the same effect on nucleosome positioning, but lesions placed at different locations behave differently, illustrating that the location of the lesion and not its shape serves as the primary determinant of the most stable DNA orientation.
Volume
55
Issue
16
First Page
2411
Last Page
2421
DOI
10.1021/acs.biochem.6b00093
Rights
“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work, see http://pubs.acs.org/doi/full/10.1021/acs.biochem.6b00093
Recommended Citation
Norabuena, Erika; Williams, Sara Barnes; Klureza, Margaret A.; Goehring, Liana J.; Gruessner, Brian; Radhakrishnan, Mala L.; Jamieson, Elizabeth R.; and Núñez, Megan E., "Effect of the Spiroiminodihydantoin Lesion on Nucleosome Stability and Positioning" (2016). Chemistry: Faculty Publications, Smith College, Northampton, MA.
https://scholarworks.smith.edu/chm_facpubs/2
Comments
Peer reviewed accepted manuscript.