Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes
Fig 5
Cells disrupted for pathways required to maintain replication fork stability are sensitive to inhibition of FEN1.
A. Clonogenic survival of cells stably expressing shRNA against MRE11A, ATM or a non-targeting control when treated with 1. B. Clonogenic survival of FaDu cells or FaDu cells with all three ATM alleles knocked-out when treated with 1. C. Clonogenic survival of FaDu cells or FaDu cells with all three ATM alleles knocked-out when treated with siRNA against FEN1. D. DNA damage response induced in cells expressing shRNA against FEN1, ATM BRCA2, FANCD2 and a non-target control. E-F. Clonogenic survival of cells disrupted for FANCD2 by shRNA (E) or genes required for PRR (UBC13, HLTF) by siRNA (F) compared to a non-target control. (G) Accumulation of Rad51 foci in cells treated with 1. Data is collected from at least 500 cells per treatment. H. Clonogenic survival of cells disrupted for genes required for HR (BRCA2, BLM) and NHEJ (DNA-PKcs) by shRNA compared to a non-target control. In each clonogenic assay, data points represent the mean of at least 3 individual repeats and the error bars represent the standard error. Significance was determined by Student t-test. ns = not significant * p < 0.05. ** p < 0.005 D. DNA damage response induced in cells expressing shRNA against FEN1, ATM and a non-target control.