SART1 modulates poly-(ADP-ribose) chain accumulation and PARP1 chromatin localization

PARP1 inhibitors (PARPis) are used for treatment of cancers with mutations in <i>BRCA1</i> or <i>BRCA2</i> that are deficient in homologous recombination. The identification of modulators of PARP1 activity is critical to understand and overcome resistance to PARPis. We integrated data from three omics-scale screens to discover new regulators of PARP1 activity. We identified SART1 and show that its silencing leads to an increase in poly-ADP ribosylation and chromatin-bound PARP1. SART1 is recruited to chromatin following DNA damage and limits PARP1 chromatin retention and activity. The SART1 N-terminus is sufficient to regulate the accumulation of PAR chains and PARP1 on chromatin, an activity dependent on the RGG/RG box. Silencing of SART1 leads to an increased sensitivity of cells to DNA damage induced by IR, irrespective of <i>BRCA1</i> status and to PARPis only in absence of <i>BRCA1</i>. These results suggest that SART1 could be clinically utilized to improve PARPi efficacy.