期刊
NUCLEIC ACIDS RESEARCH
卷 36, 期 12, 页码 4128-4136出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkn334
关键词
-
资金
- Intramural NIH HHS Funding Source: Medline
- NIEHS NIH HHS [P30 ES000267, ES05355, P01 ES005355, ES00267] Funding Source: Medline
Crotonaldehyde is a representative alpha, beta-unsaturated aldehyde endowed of mutagenic and carcinogenic properties related to its propensity to react with DNA. Cyclic crotonaldehyde-derived deoxyguanosine (CrA-PdG) adducts can undergo ring opening in duplex DNA to yield a highly reactive aldehydic moiety. Here, we demonstrate that site-specifically modified DNA oligonucleotides containing a single CrA-PdG adduct can form crosslinks with topoisomerase I (Top1), both directly and indirectly. Direct covalent complex formation between the CrA-PdG adduct and Top1 is detectable after reduction with sodium cyanoborohydride, which is consistent with the formation of a Schiff base between Top1 and the ring open aldehyde form of the adduct. In addition, we show that the CrA-PdG adduct alters the cleavage and religation activities of Top1. It suppresses Top1 cleavage complexes at the adduct site and induces both reversible and irreversible cleavage complexes adjacent to the CrA-PdG adduct. The formation of stable DNA-Top1 crosslinks and the induction of Top1 cleavage complexes by CrA-PdG are mutually exclusive. Lastly, we found that crotonaldehyde induces the formation of DNA Top1 complexes in mammalian cells, which suggests a potential relationship between formation of DNA Top1 crosslinks and the mutagenic and carcinogenic properties of crotonaldehyde.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据