Role of Poly [ADP-ribose] Polymerase 1 in Activating the Kirsten ras (KRAS) Gene in Response to Oxidative Stress.
Role of Poly [ADP-ribose] Polymerase 1 in Activating the Kirsten ras (KRAS) Gene in Response to Oxidative Stress.
复制标题
DOI：
10.3390/ijms21176237
复制
发表时间：
2020-08-28
影响因子：
5.6
通讯作者：
Xodo LE
中科院分区：
文献类型：
--
作者：
Cinque G;Ferino A;Pedersen EB;Xodo LE
在胰腺 Panc-1 癌细胞中，氧化应激的增加使包含 G4 基序的 KRAS 启动子区域中 7,8-二氢-8-氧代鸟嘌呤 (8OG) 的水平比在非 G4 基序富含 G 的基因组区域中更多。我们发现 H2O2 刺激聚[ADP-核糖]聚合酶 1 (PARP-1) 招募至 KRAS 启动子，从而有效结合局部 G4 结构。与 G4 DNA 结合后，PARP-1 会发生自动 PARylation，从而带负电。我们认为，这应该有利于 MAZ 和 hnRNP A1 招募到 KRAS 启动子，因为这两个核因子由于其等电点 >7，在生理条件下本质上是阳离子。这确实得到了 Pulldown 测定的支持，该测定表明 PARP-1、MAZ 和 hnRNP A1 与模拟 KRAS G4 结构的寡核苷酸形成多蛋白复合物。我们的数据表明，Panc-1 细胞中氧化应激的增加会激活 ROS-G4-PARP-1 轴，从而刺激 KRAS 的转录。当 siRNA 沉默 PARP-1 或 Veliparib 抑制自动 PARylation 时，KRAS 的表达下调，这一发现证实了这一机制。当 Panc-1 细胞用 H2O2 处理时，观察到 KRAS 转录的强烈上调。
In pancreatic Panc-1 cancer cells, an increase of oxidative stress enhances the level of 7,8-dihydro-8-oxoguanine (8OG) more in the KRAS promoter region containing G4 motifs than in non-G4 motif G-rich genomic regions. We found that H2O2 stimulates the recruitment to the KRAS promoter of poly [ADP-ribose] polymerase 1 (PARP-1), which efficiently binds to local G4 structures. Upon binding to G4 DNA, PARP-1 undergoes auto PARylation and thus becomes negatively charged. In our view this should favor the recruitment to the KRAS promoter of MAZ and hnRNP A1, as these two nuclear factors, because of their isoelectric points >7, are cationic in nature under physiological conditions. This is indeed supported by pulldown assays which showed that PARP-1, MAZ, and hnRNP A1 form a multiprotein complex with an oligonucleotide mimicking the KRAS G4 structure. Our data suggest that an increase of oxidative stress in Panc-1 cells activates a ROS-G4-PARP-1 axis that stimulates the transcription of KRAS. This mechanism is confirmed by the finding that when PARP-1 is silenced by siRNA or auto PARylation is inhibited by Veliparib, the expression of KRAS is downregulated. When Panc-1 cells are treated with H2O2 instead, a strong up-regulation of KRAS transcription is observed.
登录
查看更多内容
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
影响因子：
2.9
作者：
Beckett, Joshua;Burns, Jacob;Tornaletti, Silvia
通讯作者：
Tornaletti, Silvia
影响因子：
7.4
作者：
Clark, David W.;Phang, Tzu;Edwards, Michael G.;Geraci, Mark W.;Gillespie, Mark N.
通讯作者：
Gillespie, Mark N.
影响因子：
5.6
作者：
Eustermann S;Videler H;Yang JC;Cole PT;Gruszka D;Veprintsev D;Neuhaus D
通讯作者：
Neuhaus D
影响因子：
3.3
作者：
Gunderson, Camille C.;Moore, Kathleen N.
通讯作者：
Moore, Kathleen N.