HMGB1 is an architectural protein in chromatin, acting also as a signaling molecule outside the cell. Recent reports from several laboratories provided evidence that a number of both the intracellular and extracellular functions of HMGB1 may depend on redox-sensitive cysteine residues of the protein. In this study we demonstrate that redox state of HMGB1 can significantly modulate the ability of the protein to bind and bend DNA, as well as to promote DNA end-joining. We also report a high affinity binding of histone H1 to hemicatenated DNA loops and DNA minicircles. Finally, we show that reduced HMGB1 can readily displace histone H1 from DNA, while oxidized HMGB1 has limited capacity for H1 displacement. Our results suggested a novel mechanism for the HMGB1-mediated modulation of histone H1 binding to DNA. Possible biological consequences of linker histones H1 replacement by HMGB1 for the functioning of chromatin are discussed.

• MeSH
• chromatin genetika   metabolismus   MeSH
• exprese genu MeSH
• genetické vektory chemie   MeSH
• histony genetika   metabolismus   MeSH
• konkatenovaná DNA genetika   metabolismus   MeSH
• kruhová DNA genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• oxidace-redukce MeSH
• protein HMGB1 genetika   metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• skot MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH
• histony MeSH
• konkatenovaná DNA MeSH
• kruhová DNA MeSH
• protein HMGB1 MeSH
• rekombinantní proteiny MeSH

The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl(2)(isopropylamine)(1-methylimidazole)] and trans-[PtCl(2)(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH(3) groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH(3) groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.

• MeSH
• bezbuněčný systém MeSH
• cirkulární dichroismus MeSH
• DNA chemie   účinky léků   MeSH
• glutathion chemie   účinky léků   MeSH
• kultivační média chemie   MeSH
• lidé MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• spektrofotometrie ultrafialová MeSH
• stereoizomerie MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dichloro(isopropylamine)(1-methylimidazole)diplatinum(II) MeSH Prohlížeč
• DNA MeSH
• glutathion MeSH
• kultivační média MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH