TARG1和PARG的相互作用对于基因组稳定性具有保护作用。
The interplay of TARG1 and PARG protects against genomic instability.
发表日期:2023 Sep 06
作者:
Joséphine Groslambert, Evgeniia Prokhorova, Anne R Wondisford, Callum Tromans-Coia, Celeste Giansanti, Jennifer Jansen, Gyula Timinszky, Matthias Dobbelstein, Dragana Ahel, Roderick J O'Sullivan, Ivan Ahel
来源:
Cell Reports
摘要:
ADP-核糖基化的及时去除对于高效的DNA修复至关重要。然而,关于ADP-核糖水解酶还有很多待发现的内容。在这里,我们对TARG1的生理作用进行了表征,TARG1是一种可去除天冬氨酸/谷氨酸连接的ADP-核糖基化的酶。我们揭示了它在DNA损伤应答中的功能,并表明TARG1的丧失会使细胞对拓扑异构酶Ⅱ、ATR和PARP的抑制剂产生敏感性增加。此外,我们发现了一个由PARP1介导的TARG1和PARG间的合成致死相互作用,它是由ADP-核糖基化的毒性累积所驱动的,这导致了复制应激和基因组不稳定性。最后,我们展示了组蛋白PARylation因子1(HPF1)缺陷加剧了过量ADP-核糖基化引起的毒性和基因组不稳定性,表明在丝氨酸和天冬氨酸/谷氨酸连接型ADP-核糖基化途径的组分之间有着密切的相互作用。总之,我们的数据确认了TARG1作为癌细胞对PARP和PARG抑制剂反应的潜在生物标志物,并且建立了TARG1和PARG的相互作用在保护细胞免受基因组不稳定性方面的作用。版权所有 © 2023 作者们。由Elsevier公司出版,版权所有。
The timely removal of ADP-ribosylation is crucial for efficient DNA repair. However, much remains to be discovered about ADP-ribosylhydrolases. Here, we characterize the physiological role of TARG1, an ADP-ribosylhydrolase that removes aspartate/glutamate-linked ADP-ribosylation. We reveal its function in the DNA damage response and show that the loss of TARG1 sensitizes cells to inhibitors of topoisomerase II, ATR, and PARP. Furthermore, we find a PARP1-mediated synthetic lethal interaction between TARG1 and PARG, driven by the toxic accumulation of ADP-ribosylation, that induces replication stress and genomic instability. Finally, we show that histone PARylation factor 1 (HPF1) deficiency exacerbates the toxicity and genomic instability induced by excessive ADP-ribosylation, suggesting a close crosstalk between components of the serine- and aspartate/glutamate-linked ADP-ribosylation pathways. Altogether, our data identify TARG1 as a potential biomarker for the response of cancer cells to PARP and PARG inhibition and establish that the interplay of TARG1 and PARG protects cells against genomic instability.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.