title: Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.
abstract: 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.
authors.affiliation: Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Martin A M
authors.initials: MA
authors.lastname: Reijns
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rigby
authors.forename: Pleasantine
authors.initials: P
authors.lastname: Mill
authors.forename: Katy R
authors.initials: KR
authors.lastname: Astell
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: Shelagh
authors.initials: S
authors.lastname: Boyle
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.forename: Margaret
authors.initials: M
authors.lastname: Keighren
authors.forename: Fiona
authors.initials: F
authors.lastname: Kilanowski
authors.forename: Paul S
authors.initials: PS
authors.lastname: Devenney
authors.forename: David
authors.initials: D
authors.lastname: Sexton
authors.forename: Graeme
authors.initials: G
authors.lastname: Grimes
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Holt
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Lawson
authors.forename: Julia R
authors.initials: JR
authors.lastname: Dorin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D043171:Chromosomal Instability; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016914:Ribonuclease H / Q000235:genetics* / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D012265:Ribonucleotides; D016159:Tumor Suppressor Protein p53; D004259:DNA-Directed DNA Polymerase; D016914:Ribonuclease H