RNASEH2B

RNASEH2B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3P56, 3P87, 3PUF
Identifiers
Aliases	RNASEH2B, AGS2, DLEU8, ribonuclease H2 subunit B
External IDs	OMIM: 610326; MGI: 1914403; HomoloGene: 41572; GeneCards: RNASEH2B; OMA:RNASEH2B - orthologs
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q14.3 Start 50,909,747 bp[1] End 51,024,120 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14|14 D1 Start 62,530,038 bp[2] End 62,610,441 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon ganglionic eminence ventricular zone granulocyte body of pancreas monocyte olfactory zone of nasal mucosa rectum muscle layer of sigmoid colon body of uterus Top expressed in genital tubercle ventricular zone tail of embryo superior cervical ganglion medial ganglionic eminence primitive streak yolk sac right kidney embryo endocardial cushion More reference expression data BioGPS n/a
Gene ontology Molecular function RNA-DNA hybrid ribonuclease activity Cellular component ribonuclease H2 complex nucleus nucleoplasm Biological process regulation of G2/M transition of mitotic cell cycle RNA catabolic process in utero embryonic development RNA phosphodiester bond hydrolysis, endonucleolytic ribonucleotide metabolic process regulation of DNA damage checkpoint negative regulation of gene expression positive regulation of fibroblast proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 79621 67153 Ensembl ENSG00000136104 ENSMUSG00000021932 UniProt Q5TBB1 Q8N451 Q80ZV0 RefSeq (mRNA) NM_001142279 NM_024570 NM_026001 RefSeq (protein) NP_001135751 NP_078846 NP_078846.2 NP_080277 Location (UCSC) Chr 13: 50.91 – 51.02 Mb Chr 14: 62.53 – 62.61 Mb PubMed search [3] [4]
Wikidata
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Ribonuclease H2, subunit B is a protein in humans that is encoded by the RNASEH2B gene.^[5] RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C), and it degrades the RNA of RNA:DNA hybrids. The non-catalytic B subunit of RNase H2 is thought to play a role in DNA replication.^[5]

Mutations in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2).^[5][6]

RNASEH2B gene knockout in mice, leads to early embryonic lethality, hence genetically engineered mice with a premature stop codon in exon 7 Rnaseh2b was created.^[7] It was hypothesized that growth arrest was a consequence of a p53-dependent DNA damage response associated with the accumulation of single RN in genomic DNA.

Ribonucleotide accumulate in RNASEH2 null cells is a consequence of incorporation by DNA polymerases. Ribonucleotide incorporation occurs in metazoans. These lesions are harmful to mammalian cells, and their removal is required for mouse embryonic development. Lesions are single or diRN covalently incorporated into genomic DNA, at a frequency of approximately 1,000,000 sites per cell, making it the most common endogenous base lesion in the mammalian genome. These lesions are best explained by the misincorporation of the major replicative polymerases.

RNASEH2 is a genome surveillance enzyme required for ribonucleotide removal. Ribonucleotide accumulation in genomic DNA of RNASEH2 null mice implicates the RNASEH2 complex in the maintenance of genome integrity. These ribonucleotide changes are likely to be harmful, as their ribose 2’-hydroxyl group increases the susceptibility of the adjacent phosphodiester bond to hydrolysis. Actually, they ^[who?] report that the ribonucleotides are being incorporated 1 every ~7,600 nt in null cells = 1,300,000 lesions per cell. This have the same order of magnitude predicted from in vitro incorporation rates by eukaryotic replicative polymerases.

Misincorporated ribonucleotide induce DNA damage. It is not that the ribonucleotides do not prevent replication; rather, polDNA can tolerate templates with ribonucleotides, having normal early embryogenesis. The problem appears with excessive numbers of ribonucleotides. DNA damage response signaling is possibly activated by the incorporation of ribonucleotides in difficult-to-replicate regions or near other detrimental lesions. They also found chromosomal rearrangements: DNA breaks may originate by replication fork collapse or hydrolysis of RN on opposing DNA strands. Also, the marked activation of DNA damage signaling in embryos may produce a p53-mediated inhibition of proliferation that might contribute to the lethality of null embryos.

Previous studies reported only two contexts where there is stable incorporation of ribonucleotides:

1). diRibonucleotides in S. pombe may be a signal to initiate homologous recombination.

2). Ribonucleotides in mtDNA (Mouse and HeLa cells).

Low levels of ribonucleotides incorporation in the nuclear genome may be tolerated. Aberrant nucleic acid substrates, generated by repair pathways non-RNaseH2 dependent (due to reduced RNASEH2 activity in Aicardi-Goutières Syndrome) are thought to drive innate immune response ^[8]. Alternatively, ribonucleotides might induce DNA-damage response signaling that by itself may stimulates interferon production.

Ribonucleotides can be highly deleterious to the mammalian cell, causing genome instability, and that the RNASEH2 is a critical enzyme for ensuring the integrity of genomic DNA. It also calls for attention and interest towards the pathway(s) that remove ribonucleotides from genomic DNA, the site and nature of ribonucleotides, induced DNA damage, and the distribution of ribonucleotides in the genome. Knowing this, understanding may be gained about the pathological and physiological roles of RN in genomic DNA, of significance to both nucleic acid-driven autoimmunity and carcinogenesis.

• GeneReviews/NCBI/NIH/UW entry on Aicardi-Goutières Syndrome