PMC

Exploiting the synthetic lethal relationship between PArP1 and BrCA1/2 for the targeted treatment of HR-deficient human tumors. HR can serve as a backup DNA repair pathway to resolve DSBs resulting from replication fork collapse. (A) In normal cells, base modifications are repaired using base excision repair prior to S-phase entry. (B) Pharmacological inhibition of the base excision repair component PARP1 results in unrepaired SSBs, which collapse replication forks into DSBs during S-phase. The newly synthesized sister chromatid can serve as a template for HR-mediated repair in BRCA1/2-proficient cells. In BRCA1/2-deficient cancer cells HR-mediated repair of PARP inhibitor-induced DSBs in not available. Instead, error-prone repair pathways, such as NHEJ and SSA are utilized, which results in progressive genomic instability and ultimately cell death.

Exploiting synthetic lethal interactions for the treatment of human cancer. DNA damage signaling networks commonly show extensive rewiring incancercells.(A)Inp53andATM-proficient cancer cells primarily promotes apoptosis. Due to a functional proapoptotic ATM-Chk2-p53- Puma/Noxa signaling axis conventional DNA-damaging chemotherapeutics should be recommended. (B) Loss of p53 in cancer cells largely abrogates DNA damage-induced apoptosis. in these cells ATM signaling is re-directed to induce a robust cell cycle arrest following genotoxic stress. ATM-mediated homologous recombination repair remains intact in p53-deficient cancer cells. Rewiring of DNA damage-induced ATM signaling promotes cellular survival in response to DNA damage. Treatment of p53-deficient tumors should include a combination of conventional DNA-damaging chemotherapy and ATM inhibitors. (C) Loss of ATM selectively reduces the induction of the pro-apoptotic p53 target genes Puma and Noxa following genotoxic stress. induction of the cell cycle-regulatory p53 target genes p21 and Gadd45α remains intact allowing ATM-depleted cancer cells to arrest the cell cycle after DNA damage. ATM-deficient cancer cells with retained p53 expression depend on the DNA-PKcs-mediated NHEJ pathway to repair chemotherapy-induced DSBs and maintain genomic stability. Abolishing DNA-PKcs signaling in these cells results in a dramatically increased sensitivity to DNA-damaging chemotherapy. Treatment of ATM-deficient tumors with retained p53 expression should include a combination of conventional DNA-damaging chemotherapy and DNA-PKcs inhibitors. (D) The combined loss of ATM and p53 precludes the execution of functional cell cycle checkpoints in cancer cells that are exposed to DNA-damaging agents. This inability to halt progression through the cell cycle despite the presence of DNA damage ultimately results in mitotic catastrophe. p53 and ATM-deficient cancer cells should be exquisitely sensitive to treatment with conventional DNA-damaging chemotherapy.