Interstrand cross-links arising from strand breaks at true abasic sites in duplex DNA.

Abstract

Interstrand cross-links are exceptionally bioactive DNA lesions. Endogenous generation of interstrand cross-links in genomic DNA may contribute to aging, neurodegeneration, and cancer. Abasic (Ap) sites are common lesions in genomic DNA that readily undergo spontaneous and amine-catalyzed strand cleavage reactions that generate a 2,3-didehydro-2,3-dideoxyribose sugar remnant (3'ddR5p) at the 3'-terminus of the strand break. Interestingly, this strand scission process leaves an electrophilic α,β-unsaturated aldehyde residue embedded within the resulting nicked duplex. Here we present evidence that 3'ddR5p derivatives generated by spermine-catalyzed strand cleavage at Ap sites in duplex DNA can react with adenine residues on the opposing strand to generate a complex lesion consisting of an interstrand cross-link adjacent to a strand break. The cross-link blocks DNA replication by ϕ29 DNA polymerase, a highly processive polymerase enzyme that couples synthesis with strand displacement. This suggests that 3'ddR5p-derived cross-links have the potential to block critical cellular DNA transactions that require strand separation. LC-MS/MS methods developed herein provide powerful tools for studying the occurrence and properties of these cross-links in biochemical and biological systems.

• Authors: Zhiyu Yang, Nathan E Price, Kevin M Johnson, Yinsheng Wang, Kent S Gates
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 45 Issue 11 Pg. 6275-6283 (Jun 20 2017) ISSN: 1362-4962 [Electronic] England
• PMID: 28531327 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Apurinic Acid
• DNA

Topics

• Apurinic Acid (chemistry)
• DNA (chemistry)
• DNA Cleavage
• DNA Damage
• DNA Replication
• Nucleic Acid Conformation