Suppressing PAR ylation by 2′,5′‐oligoadenylate synthetase 1 inhibits DNA damage‐induced cell death

High expression of 2′,5′‐oligoadenylate synthetase 1 ( OAS 1), which adds AMP residues in 2′,5′ linkage to a variety of substrates, is observed in many cancers as a part of the interferon‐related DNA damage resistance signature ( IRDS ). Poly( ADP ‐ribose) ( PAR ) is rapidly synthesized from NAD + at sites of DNA damage to facilitate repair, but excessive PAR synthesis due to extensive DNA damage results in cell death by energy depletion and/or activation of PAR ‐dependent programmed cell death pathways. We find that OAS 1 adds AMP residues in 2′,5′ linkage to PAR , inhibiting its synthesis in vitro and reducing its accumulation in cells. Increased OAS 1 expression substantially improves cell viability following DNA ‐damaging treatments that stimulate PAR synthesis during DNA repair. We conclude that high expression of OAS 1 in cancer cells promotes their ability to survive DNA damage by attenuating PAR synthesis and thus preventing cell death.