PARP1/2

Notes

original target text: PARP1/2 inhibitor

PARP1 and PARP2 are enzymes that help cells repair single-strand breaks in DNA through a process called base excision repair. When these breaks are not repaired, they can collapse replication forks and generate double-strand breaks, which are normally fixed by a separate pathway involving proteins such as BRCA1 and BRCA2. PARP inhibitors block the catalytic activity of PARP1/2, causing single-strand breaks to accumulate and convert into double-strand breaks. In cells that already have defective double-strand break repair, most notably due to BRCA1 or BRCA2 mutations, this creates a lethal accumulation of DNA damage, a concept known as synthetic lethality, while healthy cells with intact repair machinery tolerate the effect. This selectivity underlies the use of PARP1/2 inhibition in cancers associated with deficient homologous recombination repair, including certain ovarian, breast, prostate, and pancreatic tumors. The mechanism broadly matters because it exploits an inherited or acquired vulnerability in tumor DNA repair rather than targeting a growth-signaling pathway, offering a distinct strategy for tumors that share this repair defect regardless of tissue origin.