A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate

作者：Alvarez David; Chou C James; Latella Lucia; Zeitlin Samantha G; Ku Sherman; Puri Pier Lorenzo; Dervan Peter B; Gottesfeld Joel M^*

来源：Cell Cycle, 2006, 5(14): 1537-1548.

DOI：10.4161/cc.5.14.2913

• polyamides
• cancer arrest
• polyamide-chlorambucil
• 1R-Chl
• histone H4c

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.

• 出版日期2006-7-15