Thomas, R.C., Zaksauskaite, R., Al-Kandari, N.Y. et al. (4 more authors) (2024) Second generation lethality in RNAseH2a knockout zebrafish. Nucleic Acids Research, 52 (18). pp. 11014-11028. ISSN 0305-1048
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number WELLCOME TRUST (THE) 103844/Z/14/Z BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/R015457/1 MEDICAL RESEARCH COUNCIL MR/Y000021/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 16 Oct 2024 14:29 |
Last Modified: | 16 Oct 2024 14:29 |
Published Version: | http://dx.doi.org/10.1093/nar/gkae725 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/nar/gkae725 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:218452 |