Fig. 5: ADAR1 silencing in BRCA1-mutant cells causes R-loop-dependent synthetic lethality.

A, B Clonogenic survival of SUM149 BRCA1-Mut and BRCA1-Rev cells transfected with ADAR1 siRNA (P, Pool; #1; #2) in the context of exogenous overexpression of RNase H1 (RH1). Violin plots indicate median, lower and upper quartiles; N = 6 values from individual wells, representative of n = 3 biologically-independent experiments, two-way ANOVA post hoc Dunnett’s test. P values, *[BRCA1-Mut +RH1, siADAR1-#1] = 0.0109, *[BRCA1-Rev, siADAR1-P] = 0.019, **[BRCA1-Rev, siADAR1-#1] = 0.0084, **[BRCA1-Rev, siADAR1-#2] = 0.0071, ****<0.0001. C, D Representative images and quantifications of R-loops (number of fibrillarin-negative S9.6 foci per nucleus) in SUM149 BRCA1-Mut and BRCA1-Rev cells transfected with ADAR1 siRNA (P, Pool; #1). Violin plots indicate median, lower and upper quartiles; N = 150 values from individual nuclei, representative of n = 3 biologically-independent experiments, two-way ANOVA post hoc Tukey’s test. P values, **=0.0032, ****< 0.0001. E Quantification of γ-H2AX foci in SUM149 BRCA1-Mut and BRCA1-Rev cells transfected with ADAR1 siRNA (P, Pool; #1) in the context of exogenous overexpression of RNase H1 (RH1). Violin plots indicate median, lower and upper quartiles; N = 150 values from individual nuclei, representative of n = 3 biologically-independent experiments, two-way ANOVA post hoc Dunnett’s test. P value, ****< 0.0001. siCTRL, non-targeting, negative control siRNA; siPLK1, PLK1-targeting, positive control siRNA. Source data are provided as a Source Data file.