Reactivity of the Major Product of C5′-Oxidative DNA Damage in Nucleosome Core Particles

Anup Rana, Kun Yang, Marc M. Greenberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)672-676
Number of pages5
JournalChemBioChem
Volume20
Issue number5
DOIs
StatePublished - Mar 1 2019

Keywords

  • DNA damage
  • DNA oxidation
  • mechanism
  • nucleosome core particles

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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