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PARP enzymes utilise NAD +  as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either  BRCA1  or  BRCA2 . In order to assess whether other genes implicated in NAD +  metabolism were synthetic lethal with  BRCA1  or  BRCA2  gene defects, we carried out a genetic screen, which identified a synthetic lethality between  BRCA1  and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with  BRCA -gene/PARP inhibitor synthetic lethality. SIRT/ BRCA1  synthetic lethality was reversed by genetic ablation of either  PARP1  or the histone PARylation factor-coding gene  HPF1 , implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of  BRCA -gene mutant cells.

Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency