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Gene Review

RNASEH1  -  ribonuclease H1

Homo sapiens

Synonyms: H1RNA, RNH1, RNase H1, Ribonuclease H type II, Ribonuclease H1
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Disease relevance of RNASEH1

  • Unlike the E. coli enzyme, human RNase H1 displays a strong positional preference for cleavage, i.e. it cleaves between 8 and 12 nucleotides from the 5'-RNA-3'-DNA terminus of the duplex [1].
  • The intracellular localization of the enzymes, assayed by green-fluorescent protein fusions, showed that RNase H1 was present throughout the whole cell for all cell types analyzed, whereas RNase H2 was restricted to the nucleus in all cells except the prostate cancer line 15PC3 that expressed the protein throughout the cell [2].
  • These findings also have important implications for therapy of mitochondrial dysfunctions and drug development for the structurally related RNase H of HIV [3].
  • Reverse transcriptase with concomitant ribonuclease H activity in the cell-free synthesis of branched RNA-linked msDNA of Myxococcus xanthus [4].
  • HIV-1 RT-associated ribonuclease H displays both endonuclease and 3'----5' exonuclease activity [5].

High impact information on RNASEH1

  • Stable overexpression of RNase H suppressed the DNA-fragmentation and hypermutation phenotypes [6].
  • Upon removal of the first eight nucleotides of the U1 snRNA in the particles by site-directed hydrolysis with ribonuclease H in the presence of a synthetic complementary oligodeoxynucleotide splicing is completely abolished [7].
  • Depletion of U22 from Xenopus oocytes by oligonucleotide-directed ribonuclease H targeting prevented the processing of 18S ribosomal RNA (rRNA) at both ends [8].
  • This report links RNase H1 to generation of mitochondrial DNA, providing direct support for the strand-coupled mechanism of mitochondrial DNA replication [3].
  • A fraction of the mainly nuclear RNase H1 was targeted to mitochondria, and its absence in embryos resulted in a significant decrease in mitochondrial DNA content, leading to apoptotic cell death [3].

Chemical compound and disease context of RNASEH1


Biological context of RNASEH1


Anatomical context of RNASEH1

  • Whole cell extracts of the cell lines yielded similar RNase H cleavage activity in an in vitro liquid assay, in contrast to the efficacy of the ODNs in vivo [2].
  • We have demonstrated that the 60S complex represents the assembly of two single splicing complexes on the individual introns by conversion of the 60S double splicing complexes into single 50S spliceosomes by oligodeoxynucleotide directed RNase H cleavage of the double-intron pre-mRNAs within the middle exon [18].
  • Oligodeoxynucleotides containing phosphodiester or modified internucleoside linkages were investigated with respect to their ability to be acted on by ribonuclease H activities present in a HeLa cell nuclear extract after hybridization with complementary sequences in RNA [19].
  • In the present study, the effects of DNA uracilation on (-) strand DNA synthesis, RNase H activity, and (+) strand DNA synthesis were investigated in a cell-free system [20].
  • Cellular RNase H from calf thymus and RNase H-II from Rauscher leukemia virus are likewise resistant to omicron-phenanthroline inhibition, implying non-involvement of zinc in the nucleic acid hydrolysis by these enzymes [21].

Associations of RNASEH1 with chemical compounds

  • The oxidized and NEM alkylated forms of human RNase H1 exhibited binding affinities for the heteroduplex substrate comparable with the reduced form of the enzyme [22].
  • The cysteine residues responsible for the observed redox-dependent activity of human RNase H1 were determined by site-directed mutagenesis to involve Cys(147) and Cys(148) [22].
  • Comparison of the kcat, Km, and Kd for the alanine-substituted mutants with those for human RNase H1 suggests that Lys59 and Lys60 are involved in binding to the heteroduplex and that Trp43 is responsible for properly positioning the enzyme on the substrate for catalysis [14].
  • Human RNase H1 uses one tryptophan and two lysines to position the enzyme at the 3'-DNA/5'-RNA terminus of the heteroduplex substrate [14].
  • The presence or absence of phosphate or hydroxyl groups at either the 3'-DNA or 5'-RNA terminus had no effect on the human RNase H1 cleavage pattern [14].

Physical interactions of RNASEH1


Enzymatic interactions of RNASEH1

  • Following second-strand synthesis by means of RNase H-induced nick translation by DNA polymerase I the overall yields in double-stranded cDNA were slightly higher when unfractionated cytoplasmic RNA was used as starting template [24].
  • Additionally, the RNA component of the oligo/ RNA duplex is efficiently cleaved by RNase H, the site of endonucleolytic cleavage being dictated by the length of the oligodeoxynucleoside phosphorothioate segment [25].

Regulatory relationships of RNASEH1


Other interactions of RNASEH1

  • Further studies by RNase H digestion revealed the presence of smaller TRH transcripts in the hamster testes than those in the rat testis [28].
  • Following the identification of accessible ribozyme target sites by RNase H mapping, several hammerhead ribozymes were generated that cleave with comparable efficiency two different splice forms of cyclin E mRNA and the full-length and a truncated form of E2F1 RNA, respectively [29].
  • By using RNase H to specifically fragment the IGF-II transcripts into 3' and 5' fragments, we found that the RNAs vary in size due to differences in the 5' end but not the 3' end [30].
  • Oligonucleotide-directed RNase H digestion indicated regions of 7SK RNA capable of base pairing with other nucleic acids [31].
  • The RNase H domain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase was released from recombinant DHFR-RNase H fusion protein by the action of HIV-1 protease and crystallized as large trigonal prisms that diffract x-rays to at least 2.4-A resolution [32].

Analytical, diagnostic and therapeutic context of RNASEH1


  1. Properties of cloned and expressed human RNase H1. Wu, H., Lima, W.F., Crooke, S.T. J. Biol. Chem. (1999) [Pubmed]
  2. The involvement of human ribonucleases H1 and H2 in the variation of response of cells to antisense phosphorothioate oligonucleotides. ten Asbroek, A.L., van Groenigen, M., Nooij, M., Baas, F. Eur. J. Biochem. (2002) [Pubmed]
  3. Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice. Cerritelli, S.M., Frolova, E.G., Feng, C., Grinberg, A., Love, P.E., Crouch, R.J. Mol. Cell (2003) [Pubmed]
  4. Reverse transcriptase with concomitant ribonuclease H activity in the cell-free synthesis of branched RNA-linked msDNA of Myxococcus xanthus. Lampson, B.C., Inouye, M., Inouye, S. Cell (1989) [Pubmed]
  5. HIV-1 RT-associated ribonuclease H displays both endonuclease and 3'----5' exonuclease activity. Schatz, O., Mous, J., Le Grice, S.F. EMBO J. (1990) [Pubmed]
  6. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Li, X., Manley, J.L. Cell (2005) [Pubmed]
  7. The 5' terminus of the RNA moiety of U1 small nuclear ribonucleoprotein particles is required for the splicing of messenger RNA precursors. Krämer, A., Keller, W., Appel, B., Lührmann, R. Cell (1984) [Pubmed]
  8. Requirement for intron-encoded U22 small nucleolar RNA in 18S ribosomal RNA maturation. Tycowski, K.T., Shu, M.D., Steitz, J.A. Science (1994) [Pubmed]
  9. Antisense oligonucleotides containing modified bases inhibit in vitro translation of Leishmania amazonensis mRNAs by invading the mini-exon hairpin. Compagno, D., Lampe, J.N., Bourget, C., Kutyavin, I.V., Yurchenko, L., Lukhtanov, E.A., Gorn, V.V., Gamper, H.B., Toulmé, J.J. J. Biol. Chem. (1999) [Pubmed]
  10. The effects of cysteine mutations on the reverse transcriptases of human immunodeficiency virus types 1 and 2. Hizi, A., Shaharabany, M., Tal, R., Hughes, S.H. J. Biol. Chem. (1992) [Pubmed]
  11. Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3'-azido-3'-deoxythymidine. Lacey, S.F., Reardon, J.E., Furfine, E.S., Kunkel, T.A., Bebenek, K., Eckert, K.A., Kemp, S.D., Larder, B.A. J. Biol. Chem. (1992) [Pubmed]
  12. Localization of the active site of HIV-1 reverse transcriptase-associated RNase H domain on a DNA template using site-specific generated hydroxyl radicals. Götte, M., Maier, G., Gross, H.J., Heumann, H. J. Biol. Chem. (1998) [Pubmed]
  13. Structural requirements at the catalytic site of the heteroduplex substrate for human RNase H1 catalysis. Lima, W.F., Nichols, J.G., Wu, H., Prakash, T.P., Migawa, M.T., Wyrzykiewicz, T.K., Bhat, B., Crooke, S.T. J. Biol. Chem. (2004) [Pubmed]
  14. Human RNase H1 uses one tryptophan and two lysines to position the enzyme at the 3'-DNA/5'-RNA terminus of the heteroduplex substrate. Lima, W.F., Wu, H., Nichols, J.G., Prakash, T.P., Ravikumar, V., Crooke, S.T. J. Biol. Chem. (2003) [Pubmed]
  15. Ribonuclease H1 maps to chromosome 2 and has at least three pseudogene loci in the human genome. ten Asbroek, A.L., van Groenigen, M., Jakobs, M.E., Koevoets, C., Janssen, B., Baas, F. Genomics (2002) [Pubmed]
  16. Cloning, expression, and mapping of ribonucleases H of human and mouse related to bacterial RNase HI. Cerritelli, S.M., Crouch, R.J. Genomics (1998) [Pubmed]
  17. Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex. Glavan, F., Behm-Ansmant, I., Izaurralde, E., Conti, E. EMBO J. (2006) [Pubmed]
  18. Two spliceosomes can form simultaneously and independently on synthetic double-intron messenger RNA precursors. Christofori, G., Frendewey, D., Keller, W. EMBO J. (1987) [Pubmed]
  19. Site-specific excision from RNA by RNase H and mixed-phosphate-backbone oligodeoxynucleotides. Agrawal, S., Mayrand, S.H., Zamecnik, P.C., Pederson, T. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  20. Incorporation of uracil into minus strand DNA affects the specificity of plus strand synthesis initiation during lentiviral reverse transcription. Klarmann, G.J., Chen, X., North, T.W., Preston, B.D. J. Biol. Chem. (2003) [Pubmed]
  21. Reverse transcriptase-associated ribonuclease H does not require zinc for catalysis. Modak, M.J., Srivastava, A. J. Biol. Chem. (1979) [Pubmed]
  22. Human RNase H1 activity is regulated by a unique redox switch formed between adjacent cysteines. Lima, W.F., Wu, H., Nichols, J.G., Manalili, S.M., Drader, J.J., Hofstadler, S.A., Crooke, S.T. J. Biol. Chem. (2003) [Pubmed]
  23. Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. Palaniappan, C., Wisniewski, M., Jacques, P.S., Le Grice, S.F., Fay, P.J., Bambara, R.A. J. Biol. Chem. (1997) [Pubmed]
  24. Construction and quality of cDNA libraries prepared from cytoplasmic RNA not enriched in poly(A)+RNA. Lu, X., Werner, D. Gene (1988) [Pubmed]
  25. Hybrid oligonucleotides: synthesis, biophysical properties, stability studies, and biological activity. Yu, D., Iyer, R.P., Shaw, D.R., Lisziewicz, J., Li, Y., Jiang, Z., Roskey, A., Agrawal, S. Bioorg. Med. Chem. (1996) [Pubmed]
  26. Antisense 2'-O-alkyl oligoribonucleotides are efficient inhibitors of reverse transcription. Boiziau, C., Larrouy, B., Sproat, B.S., Toulmé, J.J. Nucleic Acids Res. (1995) [Pubmed]
  27. Inhibition of potentially anti-apoptotic proteins by antisense protein kinase C-alpha (Isis 3521) and antisense bcl-2 (G3139) phosphorothioate oligodeoxynucleotides: relationship to the decreased viability of T24 bladder and PC3 prostate cancer cells. Benimetskaya, L., Miller, P., Benimetsky, S., Maciaszek, A., Guga, P., Beaucage, S.L., Wilk, A., Grajkowski, A., Halperin, A.L., Stein, C.A. Mol. Pharmacol. (2001) [Pubmed]
  28. The detection of thyrotropin-releasing hormone (TRH) and TRH receptor gene expression in Siberian hamster testes. Rao, J.N., Debeljuk, L., Bartke, A., Gao, Y.P., Wilber, J.F., Feng, P. Peptides (1997) [Pubmed]
  29. Selection and characterization of active hammerhead ribozymes targeted against cyclin E and E2F1 full-length mRNA. Grassi, G., Grassi, M., Platz, J., Bauriedel, G., Kandolf, R., Kuhn, A. Antisense Nucleic Acid Drug Dev. (2001) [Pubmed]
  30. Tissue-specific expression of insulin-like growth factor II mRNAs with distinct 5' untranslated regions. Irminger, J.C., Rosen, K.M., Humbel, R.E., Villa-Komaroff, L. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  31. Structural analyses of the 7SK ribonucleoprotein (RNP), the most abundant human small RNP of unknown function. Wassarman, D.A., Steitz, J.A. Mol. Cell. Biol. (1991) [Pubmed]
  32. Proteolytic release and crystallization of the RNase H domain of human immunodeficiency virus type 1 reverse transcriptase. Hostomska, Z., Matthews, D.A., Davies, J.F., Nodes, B.R., Hostomsky, Z. J. Biol. Chem. (1991) [Pubmed]
  33. Molecular cloning and expression of cDNA for human RNase H. Wu, H., Lima, W.F., Crooke, S.T. Antisense Nucleic Acid Drug Dev. (1998) [Pubmed]
  34. Site-specific crosslinking of mammalian U11 and u6atac to the 5' splice site of an AT-AC intron. Yu, Y.T., Steitz, J.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  35. Confirmation of the hierarchical folding of RNase H: a protein engineering study. Raschke, T.M., Kho, J., Marqusee, S. Nat. Struct. Biol. (1999) [Pubmed]
  36. Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Jiang, Z., Cote, J., Kwon, J.M., Goate, A.M., Wu, J.Y. Mol. Cell. Biol. (2000) [Pubmed]
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