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. Author manuscript; available in PMC: 2023 Jun 16.
Published in final edited form as: Mol Cell. 2022 Mar 9;82(12):2315–2334. doi: 10.1016/j.molcel.2022.02.021

Figure 6. Mechanisms of action of PARP inhibitors.

Figure 6.

(A) Synthetic lethality. The simultaneous inhibition of PARP1 activity in DNA repair by PARP inhibitors (PARPi) and loss of BRCA1/2 functionality (e.g., through genetic lesions) leads to the failure of DNA damage repair and subsequent cell death.

(B) PARPi-induced PARP1 “trapping.” Some PARPi “trap” PARP1 on DNA, thus preventing autoPARylation of PARP1 and release from the site of damaged DNA. This interferes with the catalytic cycle of PARP1 and efficient DNA damage repair. PARP1 trapping acts as a replication barrier, which impairs the progression of DNA replication forks and leads to fork stalling.

(C) Regulation of DNA replication progression by PARPi. Activated PARP1 promotes replication fork reversal and reduces replication fork speed upon replication stress (see Figure 3C). In this regard, PARPi increases replication fork speed, leading to replication stress and genome instability.