1,2,3,4-Diepoxybutane-Induced DNA鈥揚rotein Cross-Linking in Human Fibrosarcoma (HT1080) Cells
详细信息 查看全文
- 作者：Teshome B. Gherezghiher ; Xun Ming ; Peter W. Villalta ; Colin Campbell ; Natalia Y. Tretyakova
- 刊名：Journal of Proteome Research
- 出版年：2013
- 出版时间：May 3, 2013
- 年：2013
- 卷：12
- 期：5
- 页码：2151-2164
- 全文大小：566K
- 年卷期：v.12,no.5(May 3, 2013)
- ISSN：1535-3907
文摘
1,2,3,4-Diepoxybutane (DEB) is the key carcinogenic metabolite of 1,3-butadiene (BD), an important industrial and environmental chemical present in urban air and in cigarette smoke. DEB is a genotoxic bis-electrophile capable of cross-linking cellular biomolecules to form DNA鈥揇NA and DNA鈥損rotein cross-links (DPCs). In the present work, mass spectrometry-based proteomics was employed to characterize DEB-mediated DNA鈥損rotein cross-linking in human fibrosarcoma (HT1080) cells. Over 150 proteins including histones, high mobility group proteins, transcription factors, splicing factors, and tubulins were found among those covalently cross-linked to chromosomal DNA in the presence of DEB. A large portion of the cross-linked proteins are known factors involved in DNA binding, transcriptional regulation, cell signaling, DNA repair, and DNA damage response. HPLC鈥揈SI+鈥揗S/MS analysis of total proteolytic digests revealed the presence of 1-(S-cysteinyl)-4-(guan-7-yl)-2,3-butanediol conjugates, confirming that DEB forms DPCs between cysteine thiols within proteins and the N-7 guanine positions within DNA. However, relatively high concentrations of DEB were required to achieve significant DPC formation, indicating that it is a poor cross-linking agent as compared to antitumor nitrogen mustards and platinum compounds.