Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency

Bajrami, Walker et al. investigated the synthetic lethality between BRCA gene defects and inhibition of two sirtuin genes, SIRT1 or SIRT6, which was found to be associated with replication stress and increased PARylation. The authors demonstrated that the SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of PARP1 or HPF1. 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.