PDF(Pubmed)
Abstract：
Poly(ADP-ribose) polymerase 1 (PARP1) has emerged as a central target for cancer therapies due to the ability of PARP inhibitors to specifically kill tumors deficient for DNA repair by homologous recombination. Upon DNA damage, PARP1 quickly binds to DNA breaks and triggers ADP-ribosylation signaling. ADP-ribosylation is important for the recruitment of various factors to sites of damage, as well as for the timely dissociation of PARP1 from DNA breaks. Indeed, PARP1 becomes trapped at DNA breaks in the presence of PARP inhibitors, a mechanism underlying the cytotoxitiy of these inhibitors. Therefore, any cellular process influencing trapping is thought to impact PARP inhibitor efficiency, potentially leading to acquired resistance in patients treated with these drugs. There are numerous ADP-ribosylation targets after DNA damage, including PARP1 itself as well as histones. While recent findings reported that the automodification of PARP1 promotes its release from the DNA lesions, the potential impact of other ADP-ribosylated proteins on this process remains unknown. Here, we demonstrate that histone ADP-ribosylation is also crucial for the timely dissipation of PARP1 from the lesions, thus contributing to cellular resistance to PARP inhibitors. Considering the crosstalk between ADP-ribosylation and other histone marks, our findings open interesting perspectives for the development of more efficient PARP inhibitor-driven cancer therapies.
摘要：
聚(ADP-核糖)聚合酶1(PARP1)由于PARP抑制剂通过同源重组特异性杀死DNA修复缺陷的肿瘤的能力而成为癌症治疗的中心靶标。DNA损伤后,PARP1快速结合DNA断裂并触发ADP-核糖基化信号传导。ADP-核糖基化对于将各种因素募集到损伤位点是重要的，以及PARP1与DNA断裂的及时解离。的确,在PARP抑制剂的存在下，PARP1在DNA断裂处被捕获，这些抑制剂细胞毒性的潜在机制。因此,任何影响捕获的细胞过程都被认为会影响PARP抑制剂的效率，这些药物治疗的患者可能导致获得性耐药。DNA损伤后有许多ADP核糖基化靶标，包括PARP1本身以及组蛋白。虽然最近的研究发现，PARP1的自动修饰促进了它从DNA损伤中的释放，其他ADP-核糖基化蛋白对该过程的潜在影响尚不清楚.这里,我们证明组蛋白ADP-核糖基化对于PARP1从病变中及时消散也至关重要，从而导致细胞对PARP抑制剂的耐药性。考虑到ADP-核糖基化和其他组蛋白标记之间的串扰，我们的发现为开发更有效的PARP抑制剂驱动的癌症治疗打开了有趣的观点.
