NAD+生物利用度介导PARG抑制诱导的胶质瘤干细胞复制阻滞、s期检查点和凋亡。

NAR Cancer Pub Date : 2021-12-01 DOI:10.1093/narcan/zcab044
Jianfeng Li, Kate M Saville, Md Ibrahim, Xuemei Zeng, Steve McClellan, Anusha Angajala, Alison Beiser, Joel F Andrews, Mai Sun, Christopher A Koczor, Jennifer Clark, Faisal Hayat, Mikhail V Makarov, Anna Wilk, Nathan A Yates, Marie E Migaud, Robert W Sobol
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引用次数: 5

摘要

DNA损伤反应蛋白PARP1和聚(adp -核糖)糖水解酶(PARG)在胶质瘤干细胞(GSCs)中的表达升高表明胶质瘤可能是PARG抑制剂(PARGi)的独特靶点。虽然PARG诱导的细胞死亡是在与电离辐射联合使用时实现的,但作为单一药物,PARG抑制剂似乎主要是细胞抑制剂。补充NAD+前体二氢烟碱酰胺核苷(NRH)可迅速增加GSCs和胶质瘤细胞中的NAD+水平,诱导PARP1激活并轻度抑制复制叉的进展。NRH+PARGi在GSCs中引发多聚adp核糖(PAR)的过度积累、s期阻滞和凋亡,但在正常星形胶质细胞中PAR的诱导或细胞毒性很小。PAR的积累受PARP1-和PAR-相互作用蛋白的调控。XRCC1的参与强调了碱基切除修复途径在应对复制应激中的作用,而PARP1在PAR积累时与PCNA、RPA和ORC2的相互作用增强,暗示了复制相关的PARP1激活,并在复制停止、s期内checkpoint和凋亡开始时与复制前复合体蛋白组装。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

NAD<sup>+</sup> bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

NAD<sup>+</sup> bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

NAD<sup>+</sup> bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

NAD+ bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

Elevated expression of the DNA damage response proteins PARP1 and poly(ADP-ribose) glycohydrolase (PARG) in glioma stem cells (GSCs) suggests that glioma may be a unique target for PARG inhibitors (PARGi). While PARGi-induced cell death is achieved when combined with ionizing radiation, as a single agent PARG inhibitors appear to be mostly cytostatic. Supplementation with the NAD+ precursor dihydronicotinamide riboside (NRH) rapidly increased NAD+ levels in GSCs and glioma cells, inducing PARP1 activation and mild suppression of replication fork progression. Administration of NRH+PARGi triggers hyperaccumulation of poly(ADP-ribose) (PAR), intra S-phase arrest and apoptosis in GSCs but minimal PAR induction or cytotoxicity in normal astrocytes. PAR accumulation is regulated by select PARP1- and PAR-interacting proteins. The involvement of XRCC1 highlights the base excision repair pathway in responding to replication stress while enhanced interaction of PARP1 with PCNA, RPA and ORC2 upon PAR accumulation implicates replication associated PARP1 activation and assembly with pre-replication complex proteins upon initiation of replication arrest, the intra S-phase checkpoint and the onset of apoptosis.

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