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

High expression of 2′,5′‐oligoadenylate synthetase 1 (OAS1), 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 OAS1 adds AMP residues in 2′,5′ linkage to PAR, inhibiting its synthesis in vitro and reducing its accumulation in cells. Increased OAS1 expression substantially improves cell viability following DNA‐damaging treatments that stimulate PAR synthesis during DNA repair. We conclude that high expression of OAS1 in cancer cells promotes their ability to survive DNA damage by attenuating PAR synthesis and thus preventing cell death. Synopsis Elevated expression levels of a subset of interferon‐inducible genes, including OAS1, is a hallmark of many cancers. Here, OAS1 is found to suppress poly(ADPr) (PAR) accumulation by interfering with PARP1 activity, promoting the survival of cancer cells with damaged DNA, thus providing them with a selective advantage. OAS1 modifies the growing ends of PAR chains with 2′, 5′‐linked AMP residues, in vitro and in vivo , which terminates chain growth and suppresses PAR accumulation. More than half of the p42 isoform of OAS1 is located in the nuclei of normal and cancer cells. OAS1 levels negatively correlate with the PAR‐induced nuclear translocation of apoptosis‐inducing factor (AIF), which mediates the cell death pathway called parthanatos. Elevated expression of OAS1 promotes the survival of human cells treated with DNA‐damaging oxidizing and alkylating agents. Graphical Abstract The interferon‐inducible gene OAS1 inhibits poly(ADP‐ribose) chain elongation in response to DNA damaging signals, to promote survival of cancer cells despite accumulation of damaged DNA.