Genome instability consequences of RNase H2 Aicardi-Goutières syndrome alleles

• Published in: DNA repair Vol. 84; p. 102614
• Main Authors: Potenski, Catherine J., Epshtein, Anastasiya, Bianco, Christopher, Klein, Hannah L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2019
• Subjects: AGS; Alleles; Autoimmune Diseases of the Nervous System - genetics; Catalytic Domain; DNA replication; Genome instability; Genomic Instability; Humans; Loss of Function Mutation; Mutagenesis; Nervous System Malformations - genetics; Phenotype; Recombination; Ribonucleases - chemistry; Ribonucleases - genetics; Ribonucleotides; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Ribonucleotides; Recombination; DNA replication; LOH; Mutagenesis; dNTP; Genome instability; rNMP; Top1; AGS; rNTP
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2019.04.002

•AGS mutations in RNase H2 subunits can be modeled in yeast.•Some AGS alleles have no observable phenotype in yeast.•Other AGS alleles have strong negative impact on genome stability.•in vivo yeast phenotypes correlate with increased retention of rNMPs in DNA.
The RNase H2 complex is a conserved heterotrimeric enzyme that degrades RNA:DNA hybrids and promotes excision of rNMPs misincorporated during DNA replication. Failure to remove ribonucleotides from DNA leads to genomic instability in yeast and humans. The monogenic Aicardi-Goutières syndrome (AGS) results from mutation in one of several genes, among which are those encoding the RNase H2 subunits. The complete cellular and genomic consequences of RNASEH2 mutations and the precise connection to disease remain unclear. To learn more about the effect of RNASEH2 mutations on the cell, we used yeast as a model of AGS disease. We have generated yeast strains bearing AGS-associated mutations in RNASEH2 genes. There is a range of disease presentation in patients bearing these RNASEH2 variants. Here we report on in vivo phenotypes of genomic instability, including mutation and recombination rates, and synthetic gene interactions. These phenotypes provide insight into molecular consequences of RNASEH2 mutations, and lay the groundwork for further study of genomic instability as a contributing factor to AGS disease.