TY - JOUR

T1 - Dynamics of 8-Oxoguanine in DNA: Decisive Effects of Base Pairing and Nucleotide Context

AU - Ovcherenko, Sergey S

AU - Shernyukov, Andrey V

AU - Nasonov, Dmitry M

AU - Endutkin, Anton V

AU - Zharkov, Dmitry O

AU - Bagryanskaya, Elena G

N1 - Funding: This study was supported by Russian Science Foundation (21-14-00219). Partial salary support from Russian Ministry of Science and Higher Education (12103130005-8) is acknowledged.

PY - 2023/3/15

Y1 - 2023/3/15

N2 - 8-Oxo-7,8-dihydroguanine (oxoG), an abundant DNA lesion, can mispair with adenine and induce mutations. To prevent this, cells possess DNA repair glycosylases that excise either oxoG from oxoG:C pairs (bacterial Fpg, human OGG1) or A from oxoG:A mispairs (bacterial MutY, human MUTYH). Early lesion recognition steps remain murky and may include enforced base pair opening or capture of a spontaneously opened pair. We adapted the CLEANEX-PM NMR protocol to detect DNA imino proton exchange and analyzed the dynamics of oxoG:C, oxoG:A, and their undamaged counterparts in nucleotide contexts with different stacking energy. Even in a poorly stacking context, the oxoG:C pair did not open easier than G:C, arguing against extrahelical base capture by Fpg/OGG1. On the contrary, oxoG opposite A significantly populated the extrahelical state, which may assist recognition by MutY/MUTYH.

AB - 8-Oxo-7,8-dihydroguanine (oxoG), an abundant DNA lesion, can mispair with adenine and induce mutations. To prevent this, cells possess DNA repair glycosylases that excise either oxoG from oxoG:C pairs (bacterial Fpg, human OGG1) or A from oxoG:A mispairs (bacterial MutY, human MUTYH). Early lesion recognition steps remain murky and may include enforced base pair opening or capture of a spontaneously opened pair. We adapted the CLEANEX-PM NMR protocol to detect DNA imino proton exchange and analyzed the dynamics of oxoG:C, oxoG:A, and their undamaged counterparts in nucleotide contexts with different stacking energy. Even in a poorly stacking context, the oxoG:C pair did not open easier than G:C, arguing against extrahelical base capture by Fpg/OGG1. On the contrary, oxoG opposite A significantly populated the extrahelical state, which may assist recognition by MutY/MUTYH.

KW - Base Pairing

KW - DNA Repair

KW - DNA/chemistry

KW - Guanine/chemistry

KW - Humans

KW - Nucleotides

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85149386454&origin=inward&txGid=b7831bc74bd52444d36f9da89fa8ebb0

UR - https://www.mendeley.com/catalogue/29550847-2d17-31f9-8119-491677197e75/

U2 - 10.1021/jacs.2c11230

DO - 10.1021/jacs.2c11230

M3 - Article

C2 - 36867834

VL - 145

SP - 5613

EP - 5617

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 10

ER -