PUBLICATION

Second generation lethality in RNAseH2a knockout zebrafish

Authors

Thomas, R.C., Zaksauskaite, R., Al-Kandari, N.Y., Hyde, A.C., Abugable, A.A., El-Khamisy, S.F., van Eeden, F.J.

ID

ZDB-PUB-240902-14

Date

2024

Source

Nucleic acids research 52(18): 11014-11028 (Journal)

Registered Authors

Thomas, Ruth C., van Eeden, Freek

Keywords

none

MeSH Terms

Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism
Ribonucleotides/metabolism
Zebrafish*/embryology
Zebrafish*/genetics
Animals
Disease Models, Animal
Female
Testis/metabolism
Gene Knockout Techniques
Brain/embryology
Brain/metabolism
Male
Ribonuclease H*/genetics
Ribonuclease H*/metabolism
Nervous System Malformations/genetics

PubMed

39217460 Full text @ Nucleic Acids Res.

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.

Genes / Markers

Figures