期刊
BIOCHEMISTRY
卷 62, 期 16, 页码 2382-2390出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.3c00243
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Upon binding to DNA damage, PARP1 is activated to perform PARylation on itself and other proteins, leading to chromatin relaxation and DNA repair factor recruitment. HPF1 is a cofactor of PARP1 that directs preferential PARylation of histones. Understanding the dissociation of PARPi from the PARP1-HPF1 complex is important for the development of next-generation PARP inhibitors.
PARP1, upon binding to damaged DNA, is activated to performpolyADP-ribosylation (PARylation) on itself and other proteins, whichleads to relaxation of chromatin and recruitment of DNA repair factors.HPF1 was recently discovered as a protein cofactor of PARP1 that directspreferential PARylation of histones over other targets by contributingto and altering the PARP1 active site. Inhibitors of PARP1 (PARPi)are used in the treatment of BRCA-/- cancers, but thebasis for their potency in cells, especially in the context of HPF1,is not fully understood. Here, we demonstrate the simple one-stepassociation for eight different PARPi to PARP1 with measured ratesof association (k (on)) of 0.8-6 & mu;M-1 s(-1). We find only minor differencesin these on rates when comparing PARP1 with the PARP1-HPF1complex. By characterizing the rates of dissociation (k (off)) and the binding constants (K (D)) for two more recently discovered PARPi, we find, for example,that saruparib has a half-life for dissociation of 22.5 h and fluzoparibhas higher affinity for PARP1 in the presence of HPF1, just like thestructurally related compound olaparib. By using the measured K (D) and k (on) to calculate k (off), we find that the potency of PARPi in cellscorrelates best with the k (off) from thePARP1-HPF1 complex. Our data suggest that dissociation of adrug compound from the PARP1-HPF1 complex should be the parameterof choice for guiding the development of next-generation PARPi.
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