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• W2000965988 abstract "DNA replication and repair, which are critical for maintaining genome stability, depend partly on the activity of an emerging family of structure-specific endonucleases. These enzymes, typified by flap endonuclease-1 (FEN-1), are required for the removal of RNA primers during lagging-strand DNA synthesis and the damaged DNA fragments in various DNA-repair pathways[1Lieber M. BioEssays. 1997; 19: 233-240Crossref PubMed Scopus (397) Google Scholar, 2Bambara R.A. Murante R.S. Henricksen L.A. J. Biol. Chem. 1997; 272: 4647-4650Crossref PubMed Scopus (298) Google Scholar, 3Klungland A. Lindahl T. EMBO J. 1997; 16: 3341-3348Crossref Scopus (675) Google Scholar, 4Johnson R.E. Kovvali G.K. Prakash L. Prakash S. Science. 1995; 269: 238-240Crossref Scopus (195) Google Scholar, 5Tishkoff D.X. Filosi N. Gaida G.M. Kolodner R.D. Cell. 1997; 88: 253-263Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar]. To carry out these biologically essential enzymatic transformations, these nucleases must be able to cleave RNA and DNA, regardless of sequence; however, indiscriminate cleavage of substrate would be lethal to the cell. To circumvent this apparent paradox, structure-specific endonucleases recognize their substrates using a structure-based recognition mechanism, rather than a mechanism based on the chemical signatures of the constituent DNA bases. For the FEN-1 family of structure-specific endonucleases, a typical substrate is formed by the junction where two strands of duplex DNA separate, leaving a free, single-stranded 5′ arm. Work from different groups[1Lieber M. BioEssays. 1997; 19: 233-240Crossref PubMed Scopus (397) Google Scholar, 2Bambara R.A. Murante R.S. Henricksen L.A. J. Biol. Chem. 1997; 272: 4647-4650Crossref PubMed Scopus (298) Google Scholar, 6Murate R.S. Rust L. Bambara R.A. J. Biol. Chem. 1994; 270: 30377-30383Google Scholar]has demonstrated convincingly that FEN-1 specifically recognizes the 5′ single-stranded arm, regardless of sequence or composition (DNA or RNA), and then tracks down the single-stranded arm to the cleavage site, which is located at the junction of the double- and single-stranded nucleic acid. This reaction is stimulated through interactions with the processivity factor of DNA polymerase, PCNA, which might serve to localize FEN-1 to the replication machinery when performing its crucial function in vivo[7Li X. Li J. Harrington J. Lieber M.R. Burgers P.M.J. J. Biol. Chem. 1995; 270: 22109-22112Crossref PubMed Scopus (255) Google Scholar, 8Wu X. et al.Nucleic Acids Res. 1996; 24: 2036-2043Crossref Scopus (198) Google Scholar]. That FEN-1 is critical for preserving the genetic integrity of the genome is emphasized by recent work showing that fen-1 null mutants in Saccharomyces cerevisiae lead to a strong mutator phenotype owing to duplication mutations arising from the inability to process the primers associated with Okazaki fragments correctly[4Johnson R.E. Kovvali G.K. Prakash L. Prakash S. Science. 1995; 269: 238-240Crossref Scopus (195) Google Scholar, 5Tishkoff D.X. Filosi N. Gaida G.M. Kolodner R.D. Cell. 1997; 88: 253-263Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar]. Such mutations have been associated with several human disorders, such as recessive retinitis pigmentosa, lethal junctional epidermolysis bullosa, familial hypertropic cardiomyopathy and cancer. In addition, FEN-1 has an active role in preventing trinucleotide repeat (TNR)expansion and contraction, because deletion mutants in S. cerevisiae lead to length-dependent destabilization of CTG tracts and a marked increase in expansion frequency. Thus, fen-1 mutants in humans might lead to such genetic diseases as myotonic dystrophy, Huntington's disease, several ataxias and fragile X syndrome, all of which result from TNR expansion[9Freudenreich C.H. Kantrow S.M. Zakian V.A. Science. 1998; 279: 853-856Crossref Scopus (365) Google Scholar, 10Schweitzer J.K. Livingston D.M. Hum. Mol. Genet. 1998; 7: 69-74Crossref PubMed Scopus (165) Google Scholar]. Flap endonucleases are functionally conserved from virus, eubacteria, archaebacteria, low eukaryotes to mammals. Eukaryotic homologs of FEN-1 exist in cells from several organisms, including human and murine cells, as well as S. cerevisiae and Schizosaccharomyces pombe, where they have been called RAD27 (RTH1) and rad2, respectively. In eubacterial and viral systems, functional homologs have relatively low sequence similarity. These homologs include the N-terminal 5′–3′ exonuclease domains of Escherichia coli and Thermus aquaticus DNA polymerase, T4 RNaseH and T5 5′–3′ exonuclease[11Lyamichev V. Brow M.A.D. Dahlberg J.E. Science. 1993; 260: 778-783Crossref Scopus (309) Google Scholar, 12Xu Y. et al.J. Mol. Biol. 1997; 268: 284-302Crossref Scopus (53) Google Scholar, 13Ceska T.A. Sayers J.R. Stier G. Suck D. Nature. 1996; 382: 90-93Crossref Scopus (165) Google Scholar, 14Mueser T.C. Nossal N.G. Hyde C.C. Cell. 1996; 85: 1101-1112Abstract Full Text Full Text PDF Scopus (164) Google Scholar, 15Bhagwat M. Hobb L.J. Nossal N.G. J. Biol. Chem. 1997; 272: 28523-28530Crossref Scopus (21) Google Scholar]. Within this family, two nuclease domains, termed the N (N-terminal) and I (Intermediate) domains, share limited sequence similarity with FEN-1 and contain the conserved acidic amino acids that play a critical role in catalysis (Fig. 1). These domains are also homologous to regions in the XPG protein[1Lieber M. BioEssays. 1997; 19: 233-240Crossref PubMed Scopus (397) Google Scholar]. This 134-kDa nuclear protein, whose malfunction is implicated in the neurodegenerative disorder, xeroderma pigmentosum and Cockayne's syndrome, is required for both nucleotide-excision repair (NER) and transcription-coupled repair of oxidative damage[16Cooper P.K. Nouspikel T. Clarkson S.G. Leadon S.A. Science. 1997; 275: 990-993Crossref PubMed Scopus (285) Google Scholar]. We have found three new FEN-1 proteins from the archaebacteria Archaeglobius fulgidus, Methanococcus jannaschii and Pyrococcus furiosus, using characteristic patterns from eukaryotic FEN-1 homologs (Fig. 2). Unlike the eubacterial nucleases, these enzymes exist as independent proteins and share about 75% sequence similarity with the human FEN-1 enzyme in the two conserved domains indicated in Fig. 1. This is consistent with the observation that many identified archaeal DNA metabolic enzymes, such as DNA polymerases and ligases, are most-closely (or only) related in sequence to eukaryotic replication proteins[17Bult C.J. et al.Science. 1996; 273: 1058-1073Crossref Scopus (2306) Google Scholar, 18Edgell D.R. Doolittle W.F. Cell. 1997; 89: 995-998Abstract Full Text Full Text PDF Scopus (230) Google Scholar]. Importantly, amino acid residues that are critical for metal binding and substrate hydrolysis are absolutely conserved in these archaebacterial enzymes (Fig. 2). Moreover, the C-terminal domain that is absent in the eubacterial and viral enzymes, which plays an important role in mediating the interaction with PCNA, is conserved in the archaebacterial systems. Putative PCNA homologs also exist in A. fulgidus, P. furiosus and M. jannaschii (B. Shen et al., unpublished). The additional C-terminal basic residues that are unique to the eukaryotic FEN-1 homologs probably serve as a nuclear localization signal, allowing the enzyme to migrate to the nucleus where its activity is required[19Harrington J.J. Lieber M.R. Genes Dev. 1994; 8: 1344-1355Crossref Scopus (260) Google Scholar, 20Friedberg E.C. Trends Biochem. Sci. 1992; 17: 347Abstract Full Text PDF PubMed Scopus (10) Google Scholar]. Understanding the exquisite structural specificity imparted by these domains, and the roles they play in mediating FEN-1 activity in DNA replication and repair, presents an exciting problem whose solution will require integrated biochemical and structural approaches. Given the high degree of homology between the archaebacterial and eukaryotic FEN-1s, these newly discovered nucleases provide a powerful system for characterizing the biochemical properties of this crucial enzyme family. The work in Shen's laboratory is supported by an institutional fund from the City of Hope. D. H. is supported by a Graduate Fellowship from the Skaggs Institute for Research." @default.
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• W2000965988 title "Flap endonuclease homologs in archaebacteria exist as independent proteins" @default.
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