The Departments of Oncology and Experimental Medicine, The Lady Davis Institute and Segal Cancer Centre of the Jewish General Hospital, McGill University Montreal QC, Canada.
Front Pharmacol. 2012 Dec 27;3:202. doi: 10.3389/fphar.2012.00202. eCollection 2012.
Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.
聚（ADP-核糖）聚合酶（PARP）是一种负责通过添加聚（ADP-核糖）链（称为 PAR 化）来催化翻译后修饰的酶。PAR 化修饰调节多种细胞过程，包括转录、染色质重塑、细胞凋亡和 DNA 损伤修复。特别是，PARP 激活在 DNA 损伤反应中的作用已被深入研究。携带乳腺癌易感基因 Brca1/2 突变的肿瘤容易发生 DNA 断裂，其功能双链 DNA 的恢复依赖于 PARP。这一概念已在 Brca 突变的乳腺和卵巢肿瘤的治疗中得到了利用，在这些肿瘤中观察到对 PARP 抑制剂的急性敏感性。基于体外和临床研究，PARP 抑制剂在治疗 Brca 突变肿瘤之外的应用程度仍不清楚。本综述将重点讨论 PAR 化在染色质重塑、表观遗传学和转录中的经常被忽视的作用，以解释为什么一些癌症对 PARP 抑制无反应。我们预测，了解 PAR 化对基因表达的影响将为操纵 PARP 途径以获得治疗益处提供替代方法。
