PARP Inhibitor in Ovarian Cancer Therapy

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Ovarian cancer, the fifth leading cause in women malignancy and the second most commonly gynecological cancer, kills around 200,000 women per year in the world. The overall five and ten year survival rate is only 30% and 10 %, respectively. Recent evidence suggests that poly (ADP-ribose) polymerase (PARP) inhibitors can specifically suppress BRCA1 mutation-induced ovarian tumors.

PARPs are a large family of 17 proteins encoded by different genes and sharing a conserved catalytic domain in humans. Members of PARPs have been proved to participate in different cellular processes including chromatin structure modulation, nucleic acid metabolism, and apoptosis. What attracts most attention is the function of PARPs in DNA damage response, especially in the repair of DNA single-strand breaks (SSBs). When SSBs occur, using NAD⁺ as the substrate, active PARP catalyzes ADP-ribose covalently linked to the acceptor protein, forming the branched polymer of poly(ADP-ribose), namely PAR. The polymer at DNA damage sites of SSBs recruits DNA ligase III, DNA polymerase ß, and XRCC1 protein to form base excision repair (BER) complex, which fixes DNA lesions of SSBs.

Ovarian cancer, the fifth leading cause in women malignancy and the second most commonly gynecological cancer, kills around 200,000 women per year in the world. The overall five and ten year survival rate is only 30% and 10 %, respectively. Recent evidence suggests that poly (ADP-ribose) polymerase (PARP) inhibitors can specifically suppress BRCA1 mutation-induced ovarian tumors.

PARPs are a large family of 17 proteins encoded by different genes and sharing a conserved catalytic domain in humans. Members of PARPs have been proved to participate in different cellular processes including chromatin structure modulation, nucleic acid metabolism, and apoptosis. What attracts most attention is the function of PARPs in DNA damage response, especially in the repair of DNA single-strand breaks (SSBs). When SSBs occur, using NAD⁺ as the substrate, active PARP catalyzes ADP-ribose covalently linked to the acceptor protein, forming the branched polymer of poly(ADP-ribose), namely PAR. The polymer at DNA damage sites of SSBs recruits DNA ligase III, DNA polymerase ß, and XRCC1 protein to form base excision repair (BER) complex, which fixes DNA lesions of SSBs.