Description

• A cell-permeable maleimide compound selectively inhibits Werner syndrome WRN helicase activity (IC 50 = 20μM) over its ATPase and exonuclease activities (19% and <10% inhibition, respectively, at 50μM), while exhibiting no effect against the helicase activity of two other human RecQ family DNA helicases (RECQ1 and Werner syndrome BLM), Fanconi anemia group J helicase FANCJ, as well as three other E
• coli helicases, RecQ, UvrD, and DnaB
• The WRN-dependent antiproliferation activity of MIRA-1/NSC 19630 in HeLa 1.2.11 cultures (0% vs
• 95% inhibition with or without siRNA-mediated WRN-depletion, respectively, after 48 h 3μM treatment) is shown to be a direct result of apoptosis induction due to replication forks blockage (20-fold increase in PCNA foci staining after 72 h 2μM treatment), enhanced DSB (17-fold increase in γ-H2AX foci staining after 72 h 2μM treatment), and increased S-phase population (from 24% to 42% after 72 h 2μM treatment)
• In some cells, MIRA-1/NSC 19630 appears to also exert its apoptotic effect, at least in part, by restoring DNA-binding and transactivation function of some, but not all, p53 mutants.