Alexander K. Hurben, Qi Zhang, James J. Galligan, Natalia Tretyakova* and Luke Erber*,
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引用次数: 0
Abstract
Methylglyoxal (MGO) is an electrophilic α-oxoaldehyde generated endogenously through metabolism of carbohydrates and exogenously due to autoxidation of sugars, degradation of lipids, and fermentation during food and drink processing. MGO can react with nucleophilic sites within proteins and DNA to form covalent adducts. MGO-induced advanced glycation end-products such as protein and DNA adducts are thought to be involved in oxidative stress, inflammation, diabetes, cancer, renal failure, and neurodegenerative diseases. Additionally, MGO has been hypothesized to form toxic DNA–protein cross-links (DPC), but the identities of proteins participating in such cross-linking in cells have not been determined. In the present work, we quantified DPC formation in human cells exposed to MGO and identified proteins trapped on DNA upon MGO exposure using mass spectrometry-based proteomics. A total of 265 proteins were found to participate in MGO-derived DPC formation including gene products engaged in telomere organization, nucleosome assembly, and gene expression. In vitro experiments confirmed DPC formation between DNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as well as histone proteins H3.1 and H4. Collectively, our study provides the first evidence for MGO-mediated DNA–protein cross-linking in living cells, prompting future studies regarding the relevance of these toxic lesions in cancer, diabetes, and other diseases linked to elevated MGO levels.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.