Eukaryotic and prokaryotic genomes encode either Type I or Type II Ribonuclease H (RNH) which is important for processing RNA primers that prime DNA replication in almost all organisms. This review highlights the important role that Type I RNH plays in the life cycle of many retroelements, and its utility in tracing early events in retroelement evolution. Many retroelements utilize host genome-encoded RNH, but several lineages of retroelements, including some non-LTR retroposons and all LTR retrotransposons, encode their own RNH domains. Examination of these RNH domains suggests that all LTR retrotransposons acquired an enzymatically weak RNH domain that is missing an important catalytic residue found in all other RNH enzymes. We propose that this reduced activity is essential to ensure correct processing of the polypurine tract (PPT), which is an important step in the life cycle of these retrotransposons. Vertebrate retroviruses appear to have reacquired their RNH domains, which are catalytically more active, but their ancestral RNH domains (found in other LTR retrotransposons) have degenerated to give rise to the tether domains unique to vertebrate retroviruses. The tether domain may serve to control the more active RNH domain of vertebrate retroviruses. Phylogenetic analysis of the RNH domains is also useful to “date” the relative ages of LTR and non-LTR retroelements. It appears that all LTR retrotransposons are as old as, or younger than, the “youngest” lineages of non-LTR retroelements, suggesting that LTR retrotransposons arose late in eukaryotes.   

1.
Akins RA, Kelley RL, Lambowitz AM: Mitochondrial plasmids of Neurospora: integration into mitochondrial DNA and evidence for reverse transcription in mitochondria. Cell 47:505–516 (1986).
2.
Altschul SF, Koonin EV: Iterated profile searches with PSI-BLAST – a tool for discovery in protein databases. Trends Biochem Sci 23:444–447 (1998).
3.
Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402 (1997)
4.
Arkhipova IR, Pyatkov KI, Meselson M, Evgen’ev MB: Retroelements containing introns in diverse invertebrate taxa. Nat Genet 33:123–124 (2003).
5.
Artymiuk PJ, Grindley HM, Kumar K, Rice DW, Willett P: Three-dimensional structural resemblance between the ribonuclease H and connection domains of HIV reverse transcriptase and the ATPase fold revealed using graph theoretical techniques. FEBS Lett 324:15–21 (1993).
6.
Arudchandran A, Cerritelli S, Narimatsu S, Itaya M, Shin DY, Shimada Y, Crouch RJ: The absence of ribonuclease H1 or H2 alters the sensitivity of Saccharomyces cerevisiae to hydroxyurea caffeine and ethyl methanesulphonate: implications for roles of RNases H in DNA replication and repair. Genes Cells 5:789–802 (2000).
7.
Belfort M, DerbyshireV, Parker MM, Cousineau B, Lambowitz AM: Mobile introns: pathways and proteins, in Craig NL, Craigie R, Gellert M, Lambowitz AM (eds): Mobile DNA II, pp 761–783 (ASM Press, Washington DC 2002).
8.
Burke WD, Malik HS, Rich SM, Eickbush TH: Ancient lineages of non-LTR retroposons in the primitive eukaryote Giardia lamblia. Mol Biol Evol 19:619–630 (2002).
9.
Cousineau B, Smith D, Lawrence-Cavanagh S, Mueller JE, Yang J, Mills D, Manias D, Dunny G, Lambowitz AM, Belfort M: Retrohoming of a bacterial group II intron: mobility via complete reverse splicing independent of homologous DNA recombination. Cell 94:451–462 (1998).
10.
Dasgupta S, Masukata H, Tomizawa J: Multiple mechanisms for initiation of ColE1 DNA replication: DNA synthesis in the presence and absence of ribonuclease H. Cell 51:1113–1122 (1987).
11.
Eickbush TH: Mobile introns: retrohoming by complete reverse splicing. Curr Biol 9:R11–14 (1999).
12.
Eickbush TH: R2 and related site-specific Non-Long Terminal Repeat retrotransposons, in Craig NL, Craigie R, Gellert M, Lambowitz AM (eds): Mobile DNA II, pp 813–835 (ASM Press, Washington DC 2002).
13.
Eickbush TH, Malik HS: Origins and evolution of retrotransposons, in Craig NL, Craigie R, Gellert M, Lambowitz AM (eds): Mobile DNA II, pp 1111–1146 (ASM Press, Washington DC 2002).
14.
Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J: Preservation of duplicate genes by complementary degenerative mutations. Genetics 151:1531–1545 (1999).
15.
Goedken ER, Keck JL, Berger JM, Marqusee S: Divalent metal cofactor binding in the kinetic folding trajectory of Escherichia coli ribonuclease HI protein. Science 9:1914–1921 (2000).
16.
Goodwin TJ, Poulter RT: The DIRS1 group of retrotransposons. Mol Biol Evol 18:2067–2082 (2001).
17.
Henikoff JG, Henikoff S: Using substitution probabilities to improve position-specific scoring matrices. Comput Appl Biosci 12:135-143 (1996).
18.
Hillenbrand G, Staudenbauer WL: Discriminatory function of ribonuclease H in the selective initiation of plasmid DNA replication. Nucleic Acids Res 10:833–852 (1982).
19.
Ishikawa K, Okumura M, Katayanagi K, Kimura S, Kanaya S, Nakamura H, Morikawa K: Crystal structure of ribonuclease H from Thermus thermophilus HB8 refined at 2.8 A resolution. J Mol Biol 230:529–542 (1993).
20.
Kanaya S: Prokaryotic type 2 RNases H. Meth Enzymol 341:377–394 (2001).
21.
Kanaya S, Kohara A, Miura Y, Sekiguchi A, Iwai S, Inoue H, Ohtsuka E, Ikehara M: Identification of the amino acid residues involved in an active site of Escherichia coli ribonuclease H by site-directed mutagenesis. J Biol Chem 265:4615–4621 (1990).
22.
Kanaya S, Oobatake M, Liu Y: Thermal stability of Escherichia coli ribonuclease HI and its active site mutants in the presence and absence of the Mg2+ ion. Proposal of a novel catalytic role for Glu48. J Biol Chem 271:32729–32736 (1996).
23.
Katayanagi K, Miyagawa M, Matsushima M, Ishikawa M, Kanaya S, Ikehara M, Matsuzaki T, Morikawa K: Three-dimensional structure of ribonuclease H from E. coli. Nature 347:306–309 (1990).
24.
Katayanagi K, Ishikawa M, Okumura M, Ariyoshi M, Kanaya S, Kawano Y, Suzuki M, Tanaka I, Morikawa K: Crystal structures of ribonuclease HI active site mutants from Escherichia coli. J Biol Chem 268:22092–22099 (1993).
25.
Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA: Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256:1783–1790 (1992).
26.
Lai L, Yokota H, Hung LW, Kim R, Kim SH: Crystal structure of archaeal RNase HII: a homologue of human major RNase H. Structure Fold Des 8:897–904 (2000).
27.
Lampson BC, Sun J, Hsu MY, Vallejo-Ramirez J, Inouye S, Inouye M: Reverse transcriptase in a clinical strain of Escherichia coli: production of branched RNA-linked msDNA. Science 243:1033–1038 (1989).
28.
Lima TM, Lim D: Isolation and characterization of host mutants defective in msDNA synthesis: role of ribonuclease H in msDNA synthesis. Plasmid 33:235–238 (1995).
29.
Luan DD, Korman MH, Jakubczak JL, Eickbush TH: Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72:595–605 (1993).
30.
Lyozin GT, Makarova KS, Velikodvorskaja VV, Zelentsova HS, Khechumian RR, Kidwell MG, Koonin EV, Evgen’ev MB: The structure and evolution of Penelope in the virilis species group of Drosophila: an ancient lineage of retroelements. J Mol Evol 52:445–456 (2001).
31.
Ma WP, Crouch RJ: Escherichia coli RNase HI inhibits murine leukaemia virus reverse transcription in vitro and yeast retrotransposon Ty1 transposition in vivo. Genes Cells 1:581–593 (1996).
32.
Malik HS, Eickbush TH: Modular evolution of the integrase domain in the Ty3/Gypsy class of LTR-retrotransposons. J Virol 73:5186–5190 (1999).
33.
Malik HS, Eickbush TH: Phylogenetic analysis of ribonuclease H domains suggests a late chimeric origin of LTR retrotransposable elements and retroviruses. Genome Res 11:1187–1197 (2001).
34.
Malik HS, Burke WD, Eickbush TH: The age and evolution of non-LTR retrotransposable elements. Mol Biol Evol 16:793–805 (1999).
35.
Malik HS, Henikoff S, Eickbush TH: Poised for contagion: evolutionary origins of the infectious abilities of invertebrate retroviruses. Genome Res 10:1307–1318 (2000).
36.
McClure MA: Evolution of retroposons by acquisition or deletion of retrovirus-like genes. Mol Biol Evol 8:835–856 (1991).
37.
McClure MA, Donaldson E, Corro S: Potential multiple endonuclease functions and a ribonuclease H encoded in retroposon genomes. Virology 296:147–158 (2002).
38.
Murante RS, Henricksen LA, Bambara RA: Junction ribonuclease: an activity in Okazaki fragment processing. Proc Natl Acad Sci USA 95:2244–2249 (1998).
39.
Muroya A, Tsuchiya D, Ishikawa M, Haruki M, Morikawa M, Kanaya S, Morikawa K: Catalytic center of an archaeal type 2 ribonuclease H as revealed by X-ray crystallographic and mutational analyses. Protein Sci 10:707–714 (2001).
40.
Ohtani N, Haruki M, Morikawa M, Crouch RJ, Itaya M, Kanaya S: Identification of the genes encoding Mn2+-dependent RNase HII and Mg2+-dependent RNase HIII from Bacillus subtilis: classification of RNases H into three families. Biochemistry 38:605–618 (1999).
41.
Olivares M, Garcia-Perez JL, Thomas MC, Heras SR, Lopez MC: The non-LTR (long terminal repeat) retrotransposon L1Tc from Trypanosoma cruzi codes for a protein with RNase H activity. J Biol Chem 277:28025–28030 (2002).
42.
Poch O, Sauvaget I, Delarue M, Tordo N: Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 8:3867–3874 (1989).
43.
Pyatkov KI, Shostak NG, Zelentsova ES, Lyozin GT, Melekhin MI, Finnegan DJ, Kidwell MG, Evgen’ev MB: Penelope retroelements from Drosophila virilis are active after transformation of Drosophila melanogaster. Proc Natl Acad Sci USA 99:16150–16155 (2002).
44.
Rest JS, Mindell DP: Retroids in archaea: phylogeny and lateral origins. Mol Biol Evol 20:1134–1142 (2003).
45.
Sato A, Kanai A, Itaya M, Tomita M: Cooperative regulation for Okazaki fragment processing by RNase HII and FEN-1 purified from a hyperthermophilic archaeon Pyrococcus furiosus. Biochem Biophys Res Commun 309:247–252 (2003).
46.
Sevilya Z, Loya S, Hughes SH, Hizi A: The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is affected by the thumb subdomain of the small protein subunits. J Mol Biol 311:957–971 (2001).
47.
Sevilya Z, Loya S, Adir N, Hizi A: The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is modulated by residue 294 of the small subunit. Nucleic Acids Res 31:1481–1487 (2003).
48.
Shimamoto T, Shimada M, Inouye M, Inouye S: The role of ribonuclease H in multicopy single-stranded DNA synthesis in retron-Ec73 and retron-Ec107 of Escherichia coli. J Bacteriol 177:264–267 (1995).
49.
Singer MS, Gottschling DE: TLC1: template RNA component of Saccharomyces cerevisiae telomerase. Science 266:404–409 (1994).
50.
Wang H, Lambowitz AM: Reverse transcription of the Mauriceville plasmid of Neurospora. Lack of ribonuclease H activity associated with the reverse transcriptase and possible use of mitochondrial ribonuclease H. J Biol Chem 268:18951–18959 (1993).
51.
Wang H, Kennell JC, Kuiper MT, Sabourin JR, Saldanha R, Lambowitz AM: The Mauriceville plasmid of Neurospora crassa: characterization of a novel reverse transcriptase that begins cDNA synthesis at the 3′ end of template. RNA Mol Cell Biol 12:5131–5144 (1992).
52.
Xiong Y, Eickbush TH: Origin and evolution of retroelements based upon their reverse transcriptase sequences. EMBO J 9:3353–3362 (1990).
53.
Yamanaka K, ShimamotoT, Inouye S, Inouye M: Retrons, in Craig NL, Craigie R, Gellert M, Lambowitz AM (eds): Mobile DNA II, pp 784–795 (ASM Press, Washington DC 2002).
54.
Yang J, Malik HS, Eickbush TH: Identification of the endonuclease domain encoded by R2 and other site-specific non-long terminal repeat retrotransposable elements Proc Natl Acad Sci USA 96:7847–7852 (1999).
55.
Yang W, Steitz TA: Recombining the structures of HIV integrase RuvC and RNase H. Structure 3:131–134 (1995).
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