Removal of ribonucleotides from DNA by RNaseH2 is essential for genome stability, and its impacted function causes the neurodegenerative disease, Aicardi Goutières Syndrome. We have created a zebrafish rnaseh2a mutant to model this process. Surprisingly, RNaseH2a knockouts show little phenotypic abnormality at adulthood in the first generation, unlike mouse knockout models, which are early embryonic lethal. However, the second generation offspring show reduced development, increased ribonucleotide incorporation and upregulation of key inflammatory markers, resulting in both maternal and paternal embryonic lethality. Thus, neither fathers or mothers can generate viable offspring even when crossed to wild-type partners. Despite their survival, rnaseh2a−/− adults show an accumulation of ribonucleotides in both the brain and testes that is not present in early development. Our data suggest that homozygotes possess RNaseH2 independent compensatory mechanisms that are inactive or overwhelmed by the inherited ribonucleotides in their offspring, or that zebrafish have a yet unknown tolerance mechanism. Additionally, we identify ribodysgenesis, the rapid removal of rNMPs and subsequently lethal fragmentation of DNA as responsible for maternal and paternal embryonic lethality.

中文翻译：

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RNAseH2a 敲除斑马鱼的第二代致死性


RNaseH2 从 DNA 中去除核糖核苷酸对于基因组稳定性至关重要，其受影响的功能会导致神经退行性疾病 Aicardi Goutières 综合征。我们创建了一个斑马鱼 rnaseh2a 突变体来模拟这个过程。令人惊讶的是，RNaseH2a 敲除在第一代成年时几乎没有表型异常，这与小鼠敲除模型不同，小鼠敲除模型在早期胚胎中是致命的。然而，第二代后代表现出发育减少、核糖核苷酸掺入增加和关键炎症标志物上调，导致母系和父系胚胎致死。因此，即使与野生型伴侣杂交，父亲或母亲也无法产生可行的后代。尽管存活下来，但 rnaseh2a-/- 成人在大脑和睾丸中都表现出核糖核苷酸的积累，这在早期发育中是不存在的。我们的数据表明，纯合子具有不依赖 RNaseH2 的补偿机制，这些机制不活跃或被其后代中遗传的核糖核苷酸所淹没，或者斑马鱼具有尚不清楚的耐受机制。此外，我们确定了 ribodysgenesis、rNMP 的快速去除和随后的 DNA 致命片段化是导致母系和父系胚胎致死的原因。