HAMNO is a potent and selective inhibitor of replication protein A (RPA) interactions with proteins involved in the replication stress response. It has shown to significantly inhibits colony formation when combined with etoposide.
Replication protein A (RPA), a major eukaryotic ssDNA-binding protein, is essential for all metabolic processes that involve ssDNA, including DNA replication, repair, and damage signaling[1]. During DNA replication stress, RPA binds the ssDNA exposed downstream of stalled primer/template (P/T) junctions, releasing Rad6/Rad18. RPA restricted the resident PCNAs to the upstream duplex regions by physically blocking diffusion of PCNA along ssDNA, and this activity was required for efficient monoubiquitination of PCNA on DNA[2].
HAMNO is a potent and selective inhibitor of replication protein A (RPA) interactions with proteins involved in the replication stress response. HAMNO was first identified as a RPA DBD-F inhibitor. It affects RPA and ATR phosphorylation directly by inhibiting DBD-F interactions with replication stress response protein involved in activating ATR. Ser22 of RPA showed highly phosphorylated after 2 h of treatment with 20μM of etoposide, which is reduced with the addition of 2 μM HAMNO. Cancer derived UMSCC38 cells, as well as another cancer cell line, UMSCC11B, have prominent γ-H2AX staining, particularly after incubation with 20 μM HAMNO. Both UMSCC38 and OKF4 cells present increased γ-H2AX staining after addition of HAMNO, with the greatest increase in signal occurring in S-phase[3].The experiment of Fanconi anemia (FA) repair pathway, which is induced by RPA, showed that HAMNO significantly induced FANCD2 monoubiquitination and foci formation and also caused increased level of γ-H2AX and S-phase accumulation in FA-deficient cells[4].
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