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, Joel M. Gottesfeld

Research output: Contribution to journalArticle

Abstract

A polyamide-chlorambucil conjugate (1R-Chl) arrests a wide range of human cancer cell lines at the G 2/M phase of the cell cycle and downregulates histone H4c gene expression. However, an siRNA against H4c mRNA causes G 1/S arrest. Here, we report that 1R-Chl downregulates H4c prior to G 2/M arrest. G 2/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 G 2/M arrest when cells are treated with siRNAs specific for H3 or H4c.

Original languageEnglish
Pages (from-to)1537-1548
Number of pages12
JournalCell Cycle
Volume5
Issue number14
Publication statusPublished - Jul 15 2006

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Keywords

  • 1R-Chl
  • Cancer arrest
  • Histone H4c
  • Polyamide-chlorambucil
  • Polyamides

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Alvarez, D., James Chou, C., Latella, L., Zeitlin, S. G., Ku, S., Puri, P. L., Dervan, P. B., & Gottesfeld, J. M. (2006). A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate. Cell Cycle, 5(14), 1537-1548.