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Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.

ABSTRACT: 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.

SUBMITTER: Hiller B

PROVIDER: S-EPMC3409502 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.

Hiller Bjoern B Achleitner Martin M Glage Silke S Naumann Ronald R Behrendt Rayk R Roers Axel A

The Journal of experimental medicine 20120716 8

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 assoc ...[more]

PMID: 22802351

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Project description:BACKGROUND & AIMS:RNase H2 is a holoenzyme, composed of 3 subunits (ribonuclease H2 subunits A, B, and C), that cleaves RNA:DNA hybrids and removes mis-incorporated ribonucleotides from genomic DNA through ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis. METHODS:We generated mice with epithelial-specific deletion of ribonuclease H2 subunit B (H2b?IEC) and mice that also had deletion of tumor-suppressor protein p53 (H2b/p53?IEC); we compared phenotypes with those of littermate H2bfl/fl or H2b/p53fl/fl (control) mice at young and old ages. Intestinal tissues were collected and analyzed by histology. We isolated epithelial cells, generated intestinal organoids, and performed RNA sequence analyses. Mutation signatures of spontaneous tumors from H2b/p53?IEC mice were characterized by exome sequencing. We collected colorectal tumor specimens from 467 patients, measured levels of ribonuclease H2 subunit B, and associated these with patient survival times and transcriptome data. RESULTS:The H2b?IEC mice had DNA damage to intestinal epithelial cells and proliferative exhaustion of the intestinal stem cell compartment compared with controls and H2b/p53?IEC mice. However, H2b/p53?IEC mice spontaneously developed small intestine and colon carcinomas. DNA from these tumors contained T>G base substitutions at GTG trinucleotides. Analyses of transcriptomes of human colorectal tumors associated lower levels of RNase H2 with shorter survival times. CONCLUSIONS:In analyses of mice with disruption of the ribonuclease H2 subunit B gene and colorectal tumors from patients, we provide evidence that RNase H2 functions as a colorectal tumor suppressor. H2b/p53?IEC mice can be used to study the roles of RNase H2 in tissue-specific carcinogenesis.

Dataset Information

Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.

Publications

Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.

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