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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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1093\/nar\/gkae725","type":"journal-article","created":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T11:30:40Z","timestamp":1725190240000},"page":"11014-11028","source":"Crossref","is-referenced-by-count":0,"title":["Second generation lethality in RNAseH2a knockout zebrafish"],"prefix":"10.1093","volume":"52","author":[{"given":"Ruth\u00a0C","family":"Thomas","sequence":"first","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ringaile","family":"Zaksauskaite","sequence":"additional","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norah\u00a0Y","family":"Al-Kandari","sequence":"additional","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne\u00a0Cathrine","family":"Hyde","sequence":"additional","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arwa\u00a0A","family":"Abugable","sequence":"additional","affiliation":[{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2721-7763","authenticated-orcid":false,"given":"Sherif\u00a0F","family":"El-Khamisy","sequence":"additional","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"The Institute of Cancer Therapeutics, University of Bradford , BD7 1DP ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3483-8269","authenticated-orcid":false,"given":"Freek\u00a0J","family":"van\u00a0Eeden","sequence":"additional","affiliation":[{"name":"Bateson Centre, School of Biosciences, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]},{"name":"Healthy Lifespan Institute, Sheffield Institute for Neuroscience, University of Sheffield , Sheffield\u00a0 S10 2TN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,9,1]]},"reference":[{"key":"2024101409532111700_B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00928361","article-title":"Physiological concentrations of purines and pyrimidines","volume":"140","author":"Traut","year":"1994","journal-title":"Mol. 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