Exploiting Synthetic Lethal Interactions Between DNA Damage Signaling, Checkpoint Control, and p53 for Targeted Cancer Therapy - Progress in Molecular Biology - page 289

F IG . 2. Synthetic lethality in cancer treatment. (A) The concept of synthetic lethality. Two
genes are in a synthetic lethal relationship when combined inactivation results in greater cell death
than that predicted from the additive effects of each gene inactivation in isolation. (B)-(D)
Exploiting the synthetic lethal relationship between PARP1 and BRCA1/2 for the targeted treat-
ment of HR-deficient human tumors. Homologous recombination (HR) is used as a DNA repair
pathway to resolve double-strand breaks (DSBs), for example, those resulting from replication fork
collapse. (B) In normal cells, PARP1 is involved in the repair of base modifications using base
excision repair (BER) prior to S-phase entry, preventing replication forks from colliding with single-
strand breaks. (C) Pharmacological inhibition of the BER component PARP1 results in unrepaired
single-strand breaks (SSBs), which lead to DSBs when the replication forks progress during the
S-phase. In BRCA1/2-proficient cells, the newly synthesized sister chromatid can serve as a