Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.

TitleEnzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.
Publication TypeJournal Article
Year of Publication2012
AuthorsReijns, MAM, Rabe, B, Rigby, RE, Mill, P, Astell, KR, Lettice, LA, Boyle, S, Leitch, A, Keighren, M, Kilanowski, F, Devenney, PS, Sexton, D, Grimes, G, Holt, IJ, Hill, RE, Taylor, MS, Lawson, KA, Dorin, JR, Jackson, AP
JournalCell
Volume149
Issue5
Pagination1008-22
Date Published2012 May 25
ISSN1097-4172
KeywordsAnimals, 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
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.

DOI10.1016/j.cell.2012.04.011
Alternate JournalCell
Citation Key10.1016/j.cell.2012.04.011
PubMed ID22579044
PubMed Central IDPMC3383994
Grant ListMC_U105663140 / / Medical Research Council / United Kingdom
MC_U127584494 / / Medical Research Council / United Kingdom
MC_PC_U127597124 / / Medical Research Council / United Kingdom
MC_PC_U127580972 / / Medical Research Council / United Kingdom
MC_U127597124 / / Medical Research Council / United Kingdom