Poly(ADP-ribose) polymerase 1 (PARP1)

Poly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear enzyme and the cell's principal sensor of single-strand DNA breaks. Its zinc-finger domains bind the lesion, which allosterically switches on a catalytic domain that consumes nicotinamide adenine dinucleotide (NAD⁺) to build branched poly(ADP-ribose) chains on PARP1 itself and on nearby chromatin proteins. Those chains are a transient recruitment signal, drawing XRCC1 and the ligase machinery of base excision and single-strand break repair to the damage; automodification then repels PARP1 from the DNA and releases it, so PARylation is both the summons and the timer. Excessive activation is harmful in its own right — NAD⁺ consumption on this scale depletes the substrate for glycolysis and drains cellular adenosine triphosphate, and the resulting parthanatos pathway of cell death contributes to injury in ischemia and neurodegeneration.

PARP1's clinical importance rests on synthetic lethality with homologous recombination deficiency. In tumors with mutated BRCA1 or BRCA2, the double-strand breaks that arise when replication meets unrepaired single-strand damage cannot be repaired accurately, so those cells die while normal cells survive. The dominant mechanism is not loss of catalytic activity but trapping: a PARP inhibitor holds PARP1 on the DNA it has bound, and the stalled complex is what collapses the oncoming fork, which is why inhibitors are ranked clinically by trapping potency rather than enzymatic potency. This principle underpins the approval of olaparib, niraparib, rucaparib and talazoparib across ovarian cancer, breast cancer, pancreatic and prostate cancers, most often as maintenance after a platinum response. Resistance arises through reversion mutations that restore the repair gene, loss of the trapping-sensitive target, or restoration of fork protection.

Beyond DNA repair, PARP1 regulates transcription, chromatin architecture and inflammatory signaling, and NAD⁺ competition links it to sirtuin activity and mitochondrial function — a set of roles that keeps the enzyme of interest well outside oncology, and that also explains part of the toxicity of blocking it.