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Reactivity of the Major Product of C5′‐Oxidative DNA Damage in Nucleosome Core Particles
Author(s) -
Rana Anup,
Yang Kun,
Greenberg Marc M.
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800663
Subject(s) - chemistry , histone , nucleosome , dna , reactivity (psychology) , dna damage , dna repair , deoxyribose , stereochemistry , biophysics , biochemistry , biology , medicine , alternative medicine , pathology
The major pathway for DNA damage following hydrogen atom abstraction from the C5′‐position results in direct strand scission and concomitant formation of a 5′‐aldehyde‐containing nucleotide (e.g., T‐al). We determined that the half‐life of alkali‐labile T‐al in free DNA under physiological conditions varies from 5–12 days. T‐al reactivity was examined at three positions within nucleosome core particles (NCPs). β‐Elimination increased >2.5‐fold when T‐al was proximal to the lysine‐rich histone H4 tail. No difference in reactivity between free DNA and NCPs was observed when T‐al was distal from the histone tails. The position‐dependent involvement of histone tails in T‐al elimination was gleaned from experiments with sodium cyanoborohydride and histone protein variants. The enhancement of T‐al elimination in NCPs is significantly smaller than previously observed for abasic sites. Computational studies comparing elimination from T‐al and abasic sites indicate that the barrier for the rate‐determining step in the latter is 2.6 kcal mol −1 lower and is stabilized by a hydrogen bond between the C4‐hydroxy group and phosphate leaving group. The long lifetime for T‐al in NCPs, combined with what is known about its repair suggests that this DNA lesion might pose significant challenges within cells.