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

: PARP1 inhibitors (PARPis) are used for treatment of cancers with mutations in BRCA1 or BRCA2 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 BRCA1 status and to PARPis only in absence of BRCA1. These results suggest that SART1 could be clinically utilized to improve PARPi efficacy.