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Cheun, Young Kun
유전체 항상성 연구단
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New Synthetic Analogs of Nitrogen Mustard DNA Interstrand Cross-Links and Their Use to Study Lesion Bypass by DNA Polymerases

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Title
New Synthetic Analogs of Nitrogen Mustard DNA Interstrand Cross-Links and Their Use to Study Lesion Bypass by DNA Polymerases
Author(s)
Young K. Cheun; Arnold S. Groehler; Orlando D. Schärer
Publication Date
2021-07
Journal
CHEMICAL RESEARCH IN TOXICOLOGY, v.34, no.7, pp.1790 - 1799
Publisher
AMER CHEMICAL SOC
Abstract
Nitrogen mustards are a widely used class of antitumor agents that exert their cytotoxic effects through the formation of DNA interstrand cross-links (ICLs). Despite being among the first antitumor agents used, the biological responses to NM ICLs remain only partially understood. We have previously reported the generation of NM ICL mimics by incorporation of ICL precursors into DNA using solid-phase synthesis at defined positions, followed by a double reductive amination reaction. However, the structure of these mimics deviated from the native NM ICLs. Using further development of our approach, we report a new class of NM ICL mimics that only differ from their native counterpart by substitution of dG with 7-deaza-dG at the ICL. Importantly, this approach allows for the synthesis of diverse NM ICLs, illustrated here with a mimic of the adduct formed by chlorambucil. We used the newly generated ICLs in reactions with replicative and translesion synthesis DNA polymerase to demonstrate their stability and utility for functional studies. These new NM ICLs will allow for the further characterization of the biological responses to this important class of antitumor agents.
URI
https://pr.ibs.re.kr/handle/8788114/10116
DOI
10.1021/acs.chemrestox.1c00123
ISSN
0893-228X
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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