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

Nucleic Acids Research
Zhiyu YangKent S Gates

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 thes...Continue Reading

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Citations

Aug 23, 2019·Journal of Biomolecular Structure & Dynamics·Young-Ae LeeSeog K Kim
Sep 4, 2020·The Journal of Biological Chemistry·Alyssa A RodriguezBrandt F Eichman
Nov 21, 2017·Current Opinion in Chemical Biology·Zhen Yu, J A Cowan
Jul 15, 2020·DNA Repair·Katherine M Amidon, Brandt F Eichman
Jun 13, 2018·Biochemistry·Ruixiang WangMarc M Greenberg
Sep 14, 2021·Journal of the American Chemical Society·Kurt HoushKent S Gates

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Methods Mentioned

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deamination
electrophoresis
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