fig2

Figure 2. Future strategies to restore PARP inhibitor efficacy in BRCA1-deficient cells upon loss of SETD1A function. Sensitivity to PARP inhibition following loss of the BOD1L/SETD1A complex or H3K4me perturbation could potentially be restored via 3 mechanisms including: (1) inhibition of the lysine demethylases (KMD5 and LSD1) responsible for removing H3K4me; (2) inhibiting nucleases such as MRE11 to prevent DNA-end resection which facilitates HR; and (3) exploiting collateral vulnerabilities using chemotherapeutics, e.g., cisplatin. Me: Methylation; PARP: poly(ADP) ribose polymerase; HR: homologous recombination; NHEJ: non-homologous end joining; DSB: double-strand break; KDMs: lysine demethylases.