MacGilvary Nathan, Cantor Sharon B
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
DNA Repair (Amst). 2024 Dec;144:103775. doi: 10.1016/j.dnarep.2024.103775. Epub 2024 Oct 19.
The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity and/or its physical trapping of PARP1 onto DNA that perturbs not only PARP1 function in DNA repair and DNA replication, but also obstructs compensating pathways. The combined disruption of PARP1 with either of the hereditary breast and ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results in synthetic lethality. This has driven the development of PARP inhibitors as therapies for BRCA-mutant cancers. In this review, we focus on recent findings that highlight loss of PARP1 catalytic activity, rather than PARPi-induced allosteric trapping, as central to PARPi efficacy in BRCA deficient cells. However, we also review findings that PARP-trapping is an effective strategy in other genetic deficiencies. Together, we conclude that the mechanism-of-action of PARP inhibitors is not unilateral; with loss of activity or enhanced trapping differentially killing depending on the genetic context. Therefore, effectively targeting cancer cells requires an intricate understanding of their key underlying vulnerabilities.
聚（ADP - 核糖）聚合酶1（PARP1）抑制剂（PARPi）造成复制应激和/或DNA损伤的机制可能有很多种。PARPi的毒性可能源于其催化活性的丧失和/或PARP1在DNA上的物理捕获，这不仅会干扰PARP1在DNA修复和DNA复制中的功能，还会阻碍补偿途径。PARP1与遗传性乳腺癌和卵巢癌基因BRCA1或BRCA2（BRCA）中的任何一个联合破坏都会导致合成致死。这推动了PARP抑制剂作为BRCA突变癌症治疗方法的发展。在本综述中，我们重点关注最近的研究发现，这些发现强调PARP1催化活性的丧失而非PARPi诱导的变构捕获是PARPi在BRCA缺陷细胞中发挥疗效的核心。然而，我们也回顾了PARP捕获在其他遗传缺陷中是一种有效策略的研究发现。我们共同得出结论，PARP抑制剂的作用机制并非单一的；活性丧失或捕获增强会根据遗传背景以不同方式杀伤细胞。因此，有效靶向癌细胞需要对其关键的潜在脆弱性有深入的了解。
