Synthetic lethality by PARP inhibitors: new mechanism uncovered based on unresolved transcription-replication conflicts

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In a landmark study recently published in Nature , Petropoulous et al. demonstrated that synthetic lethality of poly(ADP-ribose) polymerase (PARP) inhibitors in cells with defective homologous recombination repair (HR) results predominantly from transcription replication conflicts (TRC) and not, as previously proposed, from PARP trapping on DNA 1 (Fig. 1 ). The article unveils a new mechanism behind synthetic lethality of PARP inhibitors with relevance for cancer therapy. Fig. 1 New mechanism for synthetic lethality mediated by PARP inhibitors. TRCs are a major cause of genome instability and DNA double-strand breaks (DSBs). Conflicts occur when DNA replication forks and elongating RNA polymerases collide and require PARP1, TIMELESS (TIM) and TIPIN (TIP) for resolution. PARP and TIM interact and signal TCR to the replisome. After binding to DNA lesions, PARP1 is activated and forms poly(ADP)-ribose (PAR) attached to itself and to other proteins. PARP1 inhibition or loss of PARP1, TIM or TIP results in the generation of DSBs which, in the absence of homologous repair capacity, result in cell death Full size image

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