PARP1 and PARP2 govern the DNA-damage response by catalysing the reversible post-translational modification ADP-ribosylation. During the repair of DNA lesions, PARP1 and PARP2 combine with an accessory factor HPF1, which is required for the modification of target proteins on serine residues. Although the physiological role of individual ADP-ribosylation sites is still unclear, serine ADP-ribosylation at damage sites leads to the recruitment of chromatin remodellers and repair factors to ensure efficient DNA repair. ADP-ribosylation signalling is tightly controlled by the coordinated activities of (ADP-ribosyl)glycohydrolases PARG and ARH3 that, by reversing the modification, guarantee proper kinetics of DNA repair and cell cycle re-entry. The recent advances in the structural and mechanistic understanding of ADP-ribosylation provide new insights into human physiopathology and cancer therapy.
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