Oxidative damage to epigenetically methylated sites affects DNA stability, dynamics and enzymatic demethylation

Oxidative damage to epigenetically methylated sites affects DNA stability, dynamics and enzymatic demethylation Full article

Journal

Nucleic Acids Research
ISSN: 0305-1048

Output data

Year: 2018, Volume: 46, Number: 20, Pages: 10827-10839 Pages count : 13 DOI: 10.1093/nar/gky893

Authors

Gruber David R. ¹ , Toner Joanna J. ¹ , Miears Heather L. ¹ , Shernyukov Andrey V. ^2,3 , Kiryutin Alexey S. ^3,4 , Lomzov Alexander A. ^3,5 , Endutkin Anton V. ^3,5 , Grin Inga R. ^3,5 , Petrova Darya V. ^3,5 , Kupryushkin Maxim S. ⁵ , Yurkovskaya Alexandra V. ^3,4 , Johnson Eric C. ⁶ , Okon Mark ⁷ , Bagryanskaya Elena G. ^2,3 , Zharkov Dmitry O. ^3,5 , Smirnov Serge L ¹

Affiliations

1	Chemistry Department, Western Washington University, 516 High St., Bellingham, WA 98225-9150, USA
2	N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 9 Lavrentieva Ave., Novosibirsk 630090, Russia
3	Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia
4	SB RAS International Tomography Center, 3a Institutskaya St., Novosibirsk 630090, Russia
5	SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., Novosibirsk 630090, Russia
6	Bruker Biospin, 61 Daggett Dr, San Jose, CA 95134, USA
7	Department of Biochemistry and Molecular Biology, Department of Chemistry, and Michael Smith Laboratories, University of British Columbia, Vancouver BC, V6T 1Z3, Canada

DNA damage can affect various regulatory elements of the genome, with the consequences for DNA structure, dynamics, and interaction with proteins remaining largely unexplored. We used solution NMR spectroscopy, restrained and free molecular dynamics to obtain the structures and investigate dominant motions for a set of DNA duplexes containing CpG sites permuted with combinations of 5-methylcytosine (mC), the primary epigenetic base, and 8-oxoguanine (oxoG), an abundant DNA lesion. Guanine oxidation significantly changed the motion in both hemimethylated and fully methylated DNA, increased base pair breathing, induced BI→BII transition in the backbone 3′ to the oxoG and reduced the variability of shift and tilt helical parameters. UV melting experiments corroborated the NMR and molecular dynamics results, showing significant destabilization of all methylated contexts by oxoG. Notably, some dynamic and thermodynamic effects were not additive in the fully methylated oxidized CpG, indicating that the introduced modifications interact with each other. Finally, we show that the presence of oxoG biases the recognition of methylated CpG dinucleotides by ROS1, a plant enzyme involved in epigenetic DNA demethylation, in favor of the oxidized DNA strand. Thus, the conformational and dynamic effects of spurious DNA oxidation in the regulatory CpG dinucleotide can have far-reaching biological consequences.

Gruber D.R. , Toner J.J. , Miears H.L. , Shernyukov A.V. , Kiryutin A.S. , Lomzov A.A. , Endutkin A.V. , Grin I.R. , Petrova D.V. , Kupryushkin M.S. , Yurkovskaya A.V. , Johnson E.C. , Okon M. , Bagryanskaya E.G. , Zharkov D.O. , Smirnov S.L.
Oxidative damage to epigenetically methylated sites affects DNA stability, dynamics and enzymatic demethylation
Nucleic Acids Research. 2018. V.46. N20. P.10827-10839. DOI: 10.1093/nar/gky893 WOS Scopus OpenAlex

Submitted:	Apr 1, 2018
Accepted:	Sep 20, 2018
Published online:	Oct 5, 2018

Web of science:	WOS:000456709700028
Scopus:	2-s2.0-85056609090
OpenAlex:	W2895652499

DB	Citing
OpenAlex	32
Scopus	30
Web of science	28