Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, mRNA stability and is associated with autism-spectrum disorders and cancer, vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K type homology (KH) domains. Here we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX, elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 foci formation, DNA end resection and double strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU) induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer related disorders.

中文翻译：

---

自闭症相关的vigilin耗竭会损害DNA损伤修复


Vigilin (Vgl1) 对于异染色质形成、染色体分离、mRNA 稳定性至关重要，并且与自闭症谱系障碍和癌症相关，例如，vigilin 可以抑制乳腺癌中原癌基因 c-fms 的表达。 vigilin 从酵母到人类都是保守的，是一种 RNA 结合蛋白，具有 14 个串联排列的不相同的 hnRNP K 型同源 (KH) 结构域。在这里，我们报告说，vigilin 耗尽增加了细胞对顺铂或电离辐射 (IR) 诱导的细胞死亡和 DNA 修复缺陷导致的基因组不稳定性的敏感性。 Vigilin 耗尽会延迟 IR 诱导的 γ-H2AX 去磷酸化，升高残留 53BP1 和 RIF1 灶点的水平，同时减少 Rad51 和 BRCA1 灶点形成、DNA 末端切除和双链断裂 (DSB) 修复。我们发现vigilin与DNA损伤反应（DDR）蛋白RAD51和BRCA1相互作用，并且vigilin的耗尽会损害它们向DSB位点的募集。瞬时羟基脲 (HU) 在 vi​​gilin 耗尽的细胞中诱导复制应激，增加复制叉停滞并阻止 DNA 合成的重新启动。此外，组蛋白乙酰化促进vigilin优先招募到转录活跃的基因组中的DSB。这些发现揭示了 vigilin 在 DNA 损伤修复中的新作用，对自闭症和癌症相关疾病具有影响。