PARP enzyme synthesis of protein-free poly(ADP-ribose): Implications for DNA damage signaling and repair

Poly(ADP-ribose) or PAR is a versatile signaling molecule with a broad impact on human biology. PAR is a prominent indicator of cellular DNA damage and genomic transactions such as replication and transcription. Canonically, human PARP enzymes create PAR as a modification on proteins. Recently, PARP enzymes were found to create free PAR molecules that are not attached to protein. Free PAR has been implicated in cell death signaling, but the production of free PAR was assumed to be generated by glycohydrolases breaking down protein-linked PAR into smaller fragments. The direct de novo production of free PAR by PARP1 occurs alongside the synthesis of protein-linked PAR in response to DNA damage, suggesting a more prevalent role for free PAR in DNA damage signaling. This review outlines the discovery of free PAR synthesis in biochemical reactions and in cellular models of the DNA damage response. The implications for this finding are summarized in the context of DNA damage signaling and associated processes of biomolecular condensate formation and Parthanatos cell death signaling.