Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.
Ribonucleases H (RNases H) are endonucleases which cleave the RNA moiety of RNA/DNA hybrids. Their function in mammalian cells is incompletely understood. RNase H2 mutations cause Aicardi-Goutières syndrome, an inflammatory condition clinically overlapping with lupus erythematosus. We show that RNase H2 is essential in mouse embryonic development. RNase H2-deficient cells proliferated slower than control cells and accumulated in G2/M phase due to chronic activation of a DNA damage response associated with an increased frequency of single-strand breaks, increased histone H2AX phosphorylation, and induction of p53 target genes, most prominently the cyclin-dependent kinase inhibitor 1 encoding cell cycle inhibitor p21. RNase H2-deficient cells featured an increased genomic ribonucleotide load, suggesting that unrepaired ribonucleotides trigger the DNA damage response in these cells. Collectively, we show that RNase H2 is essential to remove ribonucleotides from the mammalian genome to prevent DNA damage.
Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, 01307 Dresden, Germany.
Bjoern
B
Hiller
Martin
M
Achleitner
Silke
S
Glage
Ronald
R
Naumann
Rayk
R
Behrendt
Axel
A
Roers
D000818:Animals; D002455:Cell Division / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D016195:G2 Phase / Q000235:genetics; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D012313:RNA / Q000235:genetics / Q000378:metabolism; D016914:Ribonuclease H / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012265:Ribonucleotides / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA; D006657:Histones; D007370:Interferon Type I; D012313:RNA; D016914:Ribonuclease H; D012265:Ribonucleotides; D016159:Tumor Suppressor Protein p53; C091139:ribonuclease HII; C475961:gamma-H2AX protein, mouse