Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 12, Pages 10540-10550Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.181974
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Funding
- National Institutes of Health, Eunice Kennedy Shriver NICHD
- Wellcome Trust [081760]
- Polish Ministry of Science and Higher Education [ESRF/73/2006]
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RNase H2 cleaves RNA sequences that are part of RNA/DNA hybrids or that are incorporated into DNA, thus, preventing genomic instability and the accumulation of aberrant nucleic acid, which in humans induces Aicardi-Goutieres syndrome, a severe autoimmune disorder. The 3.1 angstrom crystal structure of human RNase H2 presented here allowed us to map the positions of all 29 mutations found in Aicardi-Goutieres syndrome patients, several of which were not visible in the previously reported mouse RNase H2. We propose the possible effects of these mutations on the protein stability and function. Bacterial and eukaryotic RNases H2 differ in composition and substrate specificity. Bacterial RNases H2 are monomeric proteins and homologs of the eukaryotic RNases H2 catalytic subunit, which in addition possesses two accessory proteins. The eukaryotic RNase H2 heterotrimeric complex recognizes RNA/DNA hybrids and (5') RNA-DNA(3')/DNA junction hybrids as substrates with similar efficiency, whereas bacterial RNases H2 are highly specialized in the recognition of the (5') RNA-DNA(3') junction and very poorly cleave RNA/DNA hybrids in the presence of Mg2+ ions. Using the crystal structure of the Thermotoga maritima RNase H2-substrate complex, we modeled the human RNase H2-substrate complex and verified the model by mutational analysis. Our model indicates that the difference in substrate preference stems from the different position of the crucial tyrosine residue involved in substrate binding and recognition.
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