Andronikou Christina, Rottenberg Sven
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland; Bern Center for Precision Medicine, University of Bern, Bern, Switzerland.
Trends Mol Med. 2021 Jul;27(7):630-642. doi: 10.1016/j.molmed.2021.04.010. Epub 2021 May 21.
Histone eviction and chromatin relaxation are important processes for efficient DNA repair. Poly(ADP) ribose (PAR) polymerase 1 (PARP1) is a key mediator of this process, and disruption of PARP1 activity has a direct impact on chromatin structure. PARP inhibitors (PARPis) have been established as a treatment for BRCA1- or BRCA2-deficient tumors. Unfortunately, PARPi resistance occurs in many patients and the underlying mechanisms are not fully understood. In particular, it remains unclear how chromatin remodelers and histone chaperones compensate for the loss of the PARylation signal. In this Opinion article, we summarize currently known mechanisms of PARPi resistance. We discuss how the study of PARP1-mediated chromatin remodeling may help in further understanding PARPi resistance and finding new therapeutic approaches to overcome it.
组蛋白移除和染色质松弛是高效DNA修复的重要过程。聚（ADP）核糖（PAR）聚合酶1（PARP1）是这一过程的关键介质，PARP1活性的破坏对染色质结构有直接影响。PARP抑制剂（PARPis）已被确立为治疗BRCA1或BRCA2缺陷型肿瘤的方法。不幸的是，许多患者会出现PARPi耐药性，其潜在机制尚未完全明确。特别是，尚不清楚染色质重塑因子和组蛋白伴侣如何补偿PARylation信号的缺失。在这篇观点文章中，我们总结了目前已知的PARPi耐药机制。我们讨论了对PARP1介导的染色质重塑的研究如何有助于进一步理解PARPi耐药性并找到克服它的新治疗方法。
