Promoter G-quadruplex sequences are targets for base oxidation and strand cleavage during hypoxia-induced transcription.
Promoter G-quadruplex sequences are targets for base oxidation and strand cleavage during hypoxia-induced transcription.
复制标题
DOI：
10.1016/j.freeradbiomed.2012.04.024
复制
发表时间：
2012-07-01
影响因子：
7.4
通讯作者：
Gillespie, Mark N.
中科院分区：
文献类型：
--
作者：
Clark, David W.;Phang, Tzu;Edwards, Michael G.;Geraci, Mark W.;Gillespie, Mark N.
G-四链体，一种在某些富含G的序列中形成的非B DNA基序，通常位于生长调节基因的转录起始位点附近。多条证据表明，在生理信号传导过程中作为第二信使产生的活性氧物质靶向特定的DNA序列进行氧化碱基修饰。由于鸟嘌呤重复序列是唯一敏感的氧化损伤，和G4序列是已知的“热点”的基因突变和DNA易位，我们假设，G4序列的目标是在缺氧信号的氧化碱基修饰。肺动脉内皮细胞中约25%的低氧调节基因的启动子内含有G4序列。染色质免疫沉淀表明，共同的碱基氧化产物8-氧代鸟嘌呤被选择性地引入G4，在启动子缺氧向上，向下，和非调节基因。此外，招募碱基切除DNA修复（BER）酶，并在这些序列中形成瞬时链断裂。转录因子Sp1，组成性结合到G4序列在常氧，驱逐8-氧代鸟嘌呤积累在缺氧暴露。阻断缺氧诱导的氧化剂产生阻止了碱基修饰和Sp1结合减少。这些研究结果表明，在缺氧的氧化应激导致氧化碱基修饰，招聘BER酶，并在G4启动子序列可能改变G4的完整性和功能的瞬时链断裂。
The G-quadruplex, a non-B DNA motif that forms in certain G-rich sequences, is often located near transcription start sites in growth regulatory genes. Multiple lines of evidence show that reactive oxygen species generated as second messengers during physiologic signaling target specific DNA sequences for oxidative base modifications. Because guanine repeats are uniquely sensitive to oxidative damage, and G4 sequences are known “hot spots” for genetic mutation and DNA translocation, we hypothesized that G4 sequences are targeted for oxidative base modifications in hypoxic signaling. Approximately 25% of hypoxia-regulated genes in pulmonary artery endothelial cells harbored G4 sequences within their promoters. Chromatin immunoprecipitation showed that common base oxidation product 8-oxoguanine was selectively introduced into G4s, in promoters of hypoxia up-, down-, and non-regulated genes. Additionally, base excision DNA repair (BER) enzymes were recruited to, and transient strand breaks formed in these sequences. Transcription factor Sp1, constitutively bound to G4 sequences in normoxia, was evicted as 8-oxoguanine accumulated during hypoxic exposure. Blocking hypoxia-induced oxidant production prevented both base modifications and decreased Sp1 binding. These findings suggest that oxidant stress in hypoxia causes oxidative base modifications, recruitment of BER enzymes, and transient strand breaks in G4 promoter sequences potentially altering G4 integrity and function.
登录
查看更多内容
影响因子：
4.8
作者：
Henle, ES;Han, ZX;Linn, S
通讯作者：
Linn, S
影响因子：
3.5
作者：
HAMMONDKOSACK, MCU;DOCHERTY, K
通讯作者：
DOCHERTY, K
影响因子：
10.5
作者：
Duquette, ML;Handa, P;Maizels, N
通讯作者：
Maizels, N
影响因子：
4.8
作者：
Gonzalez, Veronica;Guo, Kexiao;Sun, Daekyu
通讯作者：
Sun, Daekyu
DOI：
10.1111/j.1742-4658.2010.07759.x
发表时间：
2010-09
期刊：
The FEBS journal
影响因子：
--
作者：
Brooks TA;Kendrick S;Hurley L
通讯作者：
Hurley L