Nucleotide Pool Depletion Induces G-Quadruplex-Dependent Perturbation of Gene Expression.
Nucleotide Pool Depletion Induces G-Quadruplex-Dependent Perturbation of Gene Expression.
复制标题
核苷酸池的耗竭诱导基因表达的G-四链体依赖性扰动。
DOI：
10.1016/j.celrep.2015.11.039
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Sale JE
中科院分区：
文献类型：
--
作者：
Papadopoulou C;Guilbaud G;Schiavone D;Sale JE
有人提出，核苷酸库失衡会导致癌症的遗传不稳定性。在这里，我们表明，通过用羟基脲（HU）耗尽核苷酸库来减缓复制叉也可以引起DT40细胞中报告基因座BU-1的短暂和永久表观遗传不稳定性。 HU 诱导分裂细胞中随机形成 Bu-1low 变体，这些变体失去了未处理细胞中存在的 H3K4me3。这种不稳定性因基因内 G 四链体而增强，该四链体还促进局部 H2Ax 磷酸化和瞬时异染色质化。 HU 诱导的全基因组基因表达变化与 G4 解旋酶 FANCJ、WRN 和 BLM 缺失引起的基因表达变化显着重叠。因此，由核苷酸库耗尽引起的全局复制应激的影响可以通过G四链体形成引起的局部复制障碍来集中，从而诱导表观遗传不稳定和基因表达的变化，这种机制可能有助于癌症中选择性转录变化。羟基脲 (HU) 随机干扰基因表达 G 四链体 (G4) 形成增强 HU 诱导的表观遗传变化 HU 诱导 G4 依赖性 DNA 损伤和异染色质形成 HU 和 G4 解旋酶突变导致类似的表达变化 通过耗尽核苷酸库减缓复制叉，增强 G 四链体在复制过程中随机干扰基因表达的能力。帕帕佐普卢等人。发现一个常见的全局复制应激源与局部 DNA 二级结构相互作用，导致表观遗传不稳定。
Nucleotide pool imbalance has been proposed to drive genetic instability in cancer. Here, we show that slowing replication forks by depleting nucleotide pools with hydroxyurea (HU) can also give rise to both transient and permanent epigenetic instability of a reporter locus, BU-1, in DT40 cells. HU induces stochastic formation of Bu-1low variants in dividing cells, which have lost the H3K4me3 present in untreated cells. This instability is potentiated by an intragenic G quadruplex, which also promotes local H2Ax phosphorylation and transient heterochromatinization. Genome-wide, gene expression changes induced by HU significantly overlap with those resulting from loss of the G4-helicases FANCJ, WRN, and BLM. Thus, the effects of global replication stress induced by nucleotide pool depletion can be focused by local replication impediments caused by G quadruplex formation to induce epigenetic instability and changes in gene expression, a mechanism that may contribute to selectable transcriptional changes in cancer. Hydroxyurea (HU) stochastically perturbs gene expression G quadruplex (G4) formation potentiates HU-induced epigenetic changes HU induces G4-dependent DNA damage and heterochromatin formation HU and G4 helicase mutations cause similar changes in expression Slowing replication forks by depleting nucleotide pools enhances the ability of G quadruplexes to stochastically perturb gene expression during replication. Papadopoulou et al. find that a common global replication stressor interacts with local DNA secondary structures to cause epigenetic instability.