Processing of an HIV Replication Intermediate by the Human DNA Replication Enzyme FEN1*

The role of human FEN1 (flapendonuclease-1), an RTH1 (RADtwo homolog-1) class nuclease, in the replication of human immunodeficiency virus (HIV) type 1 has been examined using model substrates. FEN1 is able to endonucleolytically cleave a primer annealed to a template, but with a 5′-unannealed tail. The HIV (+)-strand is synthesized as two discontinuous segments, with the upstream segment displacing the downstream segment to form a central (+)-strand overlap. Given a substrate with the exact HIV nucleotide sequence, FEN1 was able to remove the overlap. After extension of the upstream primer with DNA polymerase ε, human DNA ligase I was able to complete the continuous double strand as would occur for an integrated provirus. FEN1 may represent a target for new therapeutic interventions.

[1]  M. Gefter,et al.  DNA Replication , 2019, Advances in Experimental Medicine and Biology.

[2]  V. Zakian,et al.  Expansion and length-dependent fragility of CTG repeats in yeast. , 1998, Science.

[3]  R. Bambara,et al.  Creation and Removal of Embedded Ribonucleotides in Chromosomal DNA during Mammalian Okazaki Fragment Processing* , 1997, The Journal of Biological Chemistry.

[4]  B. Reid,et al.  Solution structure of r(gaggacug):d(CAGTCCTC) hybrid: implications for the initiation of HIV-1 (+)-strand synthesis. , 1997, Journal of molecular biology.

[5]  R. Bambara,et al.  Enzymes and Reactions at the Eukaryotic DNA Replication Fork* , 1997, The Journal of Biological Chemistry.

[6]  R. Bambara,et al.  Human RAD2 Homolog 1 5′- to 3′-Exo/Endonuclease Can Efficiently Excise a Displaced DNA Fragment Containing a 5′-Terminal Abasic Lesion by Endonuclease Activity* , 1996, The Journal of Biological Chemistry.

[7]  R. Bambara,et al.  Strand Displacement Synthesis in the Central Polypurine Tract Region of HIV-1 Promotes DNA to DNA Strand Transfer Recombination* , 1996, The Journal of Biological Chemistry.

[8]  A. Wahl,et al.  Mechanism of Tracking and Cleavage of Adduct-damaged DNA Substrates by the Mammalian 5′- to 3′-Exonuclease/Endonuclease RAD2 Homologue 1 or Flap Endonuclease 1* , 1996, The Journal of Biological Chemistry.

[9]  R. Bambara,et al.  Calf RTH-1 Nuclease Can Remove the Initiator RNAs of Okazaki Fragments by Endonuclease Activity* , 1996, The Journal of Biological Chemistry.

[10]  R. Lin,et al.  Role of calf RTH-1 nuclease in removal of 5'-ribonucleotides during Okazaki fragment processing. , 1996, Biochemistry.

[11]  R. Bambara,et al.  Calf 5′ to 3′ Exo/Endonuclease Must Slide from a 5′ End of the Substrate to Perform Structure-specific Cleavage (*) , 1995, The Journal of Biological Chemistry.

[12]  G. Biamonti,et al.  The N‐terminal domain of human DNA ligase I contains the nuclear localization signal and directs the enzyme to sites of DNA replication. , 1995, The EMBO journal.

[13]  Michael R. Green,et al.  A human nucleoporin-like protein that specifically interacts with HIV Rev , 1995, Nature.

[14]  Robert E. Johnson,et al.  Requirement of the yeast RTH1 5' to 3' exonuclease for the stability of simple repetitive DNA. , 1995, Science.

[15]  F. Bushman,et al.  Human immunodeficiency virus type 1 preintegration complexes containing discontinuous plus strands are competent to integrate in vitro , 1995, Journal of virology.

[16]  B. Dujon,et al.  Conditional Lethality of Null Mutations in RTH1 That Encodes the Yeast Counterpart of a Mammalian 5′- to 3′-Exonuclease Required for Lagging Strand DNA Synthesis in Reconstituted Systems (*) , 1995, The Journal of Biological Chemistry.

[17]  C. Pittenger,et al.  Characterization of a mutant strain of Saccharomyces cerevisiae with a deletion of the RAD27 gene, a structural homolog of the RAD2 nucleotide excision repair gene , 1995, Journal of bacteriology.

[18]  G. Crabtree,et al.  Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. , 1994, Science.

[19]  J. Turchi,et al.  Enzymatic completion of mammalian lagging-strand DNA replication. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. West,et al.  XPG endonuclease makes the 3′ incision in human DNA nucleotide excision repair , 1994, Nature.

[21]  H. Buc,et al.  HIV-1 reverse transcription. A termination step at the center of the genome. , 1994, Journal of molecular biology.

[22]  P. Brown,et al.  DNA strand exchange and selective DNA annealing promoted by the human immunodeficiency virus type 1 nucleocapsid protein , 1994, Journal of virology.

[23]  M. Wold,et al.  Recombinant replication protein A: expression, complex formation, and functional characterization. , 1994, The Journal of biological chemistry.

[24]  M. Lieber,et al.  The characterization of a mammalian DNA structure‐specific endonuclease. , 1994, The EMBO journal.

[25]  J. Turchi,et al.  The calf 5'- to 3'-exonuclease is also an endonuclease with both activities dependent on primers annealed upstream of the point of cleavage. , 1994, The Journal of biological chemistry.

[26]  T. Prolla,et al.  Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene , 1994, Molecular and cellular biology.

[27]  T. Date,et al.  Expression of active human DNA ligase I in Escherichia coli cells that harbor a full-length DNA ligase I cDNA construct. , 1993, The Journal of biological chemistry.

[28]  C. McHenry,et al.  HIV nucleocapsid protein. Expression in Escherichia coli, purification, and characterization. , 1993, The Journal of biological chemistry.

[29]  S. H. Wilson,et al.  Short gap-filling synthesis by DNA polymerase beta is processive. , 1993, The Journal of biological chemistry.

[30]  J. Turchi,et al.  Completion of mammalian lagging strand DNA replication using purified proteins. , 1993, The Journal of biological chemistry.

[31]  G. Klarmann,et al.  Template-directed pausing of DNA synthesis by HIV-1 reverse transcriptase during polymerization of HIV-1 sequences in vitro. , 1993, The Journal of biological chemistry.

[32]  P. Brown,et al.  Characterization of human immunodeficiency virus type 1 integrase expressed in Escherichia coli and analysis of variants with amino-terminal mutations , 1993, Journal of virology.

[33]  R. Reenan,et al.  Characterization of insertion mutations in the Saccharomyces cerevisiae MSH1 and MSH2 genes: evidence for separate mitochondrial and nuclear functions. , 1992, Genetics.

[34]  G. Siegal,et al.  A 5' to 3' exonuclease functionally interacts with calf DNA polymerase epsilon. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. Grinde,et al.  Mutations in the central polypurine tract of HIV-1 result in delayed replication. , 1992, Virology.

[36]  P. Charneau,et al.  A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication , 1992, Journal of virology.

[37]  D. Giedroc,et al.  Recombinant human immunodeficiency virus type 1 nucleocapsid (NCp7) protein unwinds tRNA. , 1992, The Journal of biological chemistry.

[38]  P. Brown,et al.  Reversal of integration and DNA splicing mediated by integrase of human immunodeficiency virus. , 1992, Science.

[39]  P. Charneau,et al.  A single-stranded gap in human immunodeficiency virus unintegrated linear DNA defined by a central copy of the polypurine tract , 1991, Journal of virology.

[40]  J. Hartley,et al.  Inhibition of RNase H activity and viral replication by single mutations in the 3' region of Moloney murine leukemia virus reverse transcriptase , 1989, Journal of virology.

[41]  R. Desrosiers,et al.  Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses , 1987, Nature.

[42]  A. Haase,et al.  Nucleotide sequence of the visna lentivirus: relationship to the AIDS virus , 1985, Cell.

[43]  Mark L. Pearson,et al.  Complete nucleotide sequence of the AIDS virus, HTLV-III , 1985, Nature.

[44]  A. Skalka,et al.  Products of reverse transcription in avian retrovirus analyzed by electron microscopy , 1982, Journal of virology.

[45]  E. Arts,et al.  Interaction of retroviral reverse transcriptase with template-primer duplexes during replication. , 1998, Progress in nucleic acid research and molecular biology.

[46]  M. Greaves,et al.  The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus , 1984, Nature.