A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate
Abstract
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 downregulates histone H4c gene expression. However, an siRNA against H4c mRNA causes G1/S arrest. Here, we report that 1R-Chl downregulates 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.
Additional Information
© 2006 Landes Bioscience. Original manuscript submitted: 04/11/06. Manuscript accepted: 05/17/06. We thank Malcolm Wood and William B. Kiosses of the Scripps Microscopy Facility for help with the immunofluorescence studies. This work was supported by a grant from the National Institutes of Health (CA107311 to J.M.G. and P.B.D.). We thank Paramjit Arora, Ben Edelson, Liliane Dickinson and Christian Melander for their contributions to the early phase of this work. We also thank Nick Nichols, Jim Puckett, and Curt Wittenberg for their critical comments.Additional details
- Eprint ID
- 66755
- Resolver ID
- CaltechAUTHORS:20160509-110451614
- CA107311
- National Cancer Institute
- Created
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2016-05-17Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field