Stable Interstrand Cross-Links Generated from the Repair of 1,-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Apr 4

PMID 38573229

Authors

Jie Wang

Nathania A Takyi

Yun-Chung Hsiao

Qi Tang

Yi-Tzai Chen

Chih-Wei Liu

Jian Ma

Rui Qi

Ke Bian

Zhiyuan Peng

John M Essigmann

Kun Lu

Stacey D Wetmore

Deyu Li

Affiliations

Soon will be listed here.

Abstract

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic -amino group of adenine or the -amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

Citing Articles

Repair of genomic interstrand crosslinks.

Bellani M, Shaik A, Majumdar I, Ling C, Seidman M DNA Repair (Amst). 2024; 141:103739.

PMID: 39106540 PMC: 11423799. DOI: 10.1016/j.dnarep.2024.103739.

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