title: 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alvarez
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
authors.forename: Samantha G
authors.initials: SG
authors.lastname: Zeitlin
authors.forename: Sherman
authors.initials: S
authors.lastname: Ku
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002699:Chlorambucil / Q000494:pharmacology* / Q000627:therapeutic use; D016195:G2 Phase; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007399:Interphase; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D011108:Polymers / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D006657:Histones; D011108:Polymers; D034741:RNA, Small Interfering; D002699:Chlorambucil