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A Two-Hit Mechanism for Pre-Mitotic Arrest of Cancer Cell Proliferation by a Polyamide-Alkylator Conjugate
David Alvarez, C. James Chou, Lucia Latella, Samantha G. Zeitlin, Sherman Ku, Pier Lorenzo Puri, Peter B. Dervan and Joel M. Gottesfeld
volume 5 | issue 14
15 july 2006Pages: 1537 - 1548
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A polyamide-chlorambucil conjugate (1R-Chl) arrests a wide range of human cancer cell lines at the G2/M phase of the cell cycle and down-regulates histone H4c gene expression. However, an siRNA against H4c mRNA causes G1/S arrest. Here, we report that 1R-Chl down-regulates H4c prior to G2/M arrest. G2/M arrest is the result of extensive DNA damage by 1R-Chl, which leads to phosphorylation of H2A.X at serine 139, recruitment of the Nbs1 repair protein, and a cascade of unknown events culminating with cdc2 phosphorylation at tyrosine 15 and abolishment of cdc2 kinase activity. A control polyamide-Chl conjugate, which neither binds to the H4c gene nor has an anti-proliferative effect by itself, causes G2/M arrest when cells are treated with siRNAs specific for H3 or H4c.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.