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The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.

Original publication

DOI

10.1016/j.cell.2012.04.011

Type

Journal article

Journal

Cell

Publication Date

25/05/2012

Volume

149

Pages

1008 - 1022

Keywords

Animals, Chromosomal Instability, DNA Replication, DNA-Directed DNA Polymerase, Embryo, Mammalian, Embryonic Stem Cells, Female, Male, Mice, Mice, Inbred C57BL, Ribonuclease H, Ribonucleotides, Tumor Suppressor Protein p53