An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3′ mispaired DNA

Human apurinic/apyrimidinic endonuclease (APE1) is an essential enzyme in DNA base excision repair that cuts the DNA backbone immediately adjacent to the 5′ side of abasic sites to facilitate repair synthesis by DNA polymerase β (ref. 1). Mice lacking the murine homologue of APE1 die at an early embryonic stage. Here we report that APE1 has a DNA exonuclease activity on mismatched deoxyribonucleotides at the 3′ termini of nicked or gapped DNA molecules. The efficiency of this activity is inversely proportional to the gap size in DNA. In a base excision repair system reconstituted in vitro, the rejoining of nicked mismatched DNA depended on the presence of APE1, indicating that APE1 may increase the fidelity of base excision repair and may represent a new 3′ mispaired DNA repair mechanism. The exonuclease activity of APE1 can remove the anti-HIV nucleoside analogues 3′-azido-3′-deoxythymidine and 2′,3′-didehydro-2′, 3′-dideoxythymidine from DNA, suggesting that APE1 might have an impact on the therapeutic index of antiviral compounds in this category.

[1]  Y. Cheng,et al.  Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. , 1995, Cancer research.

[2]  Chin-Ho Chen,et al.  DNA Polymerases versus HIV Reverse Transcriptase in AIDS Therapy , 1990, Annals of the New York Academy of Sciences.

[3]  H. Noller,et al.  Functional sites of interaction between release factor RF1 and the ribosome , 2000, Nature Structural Biology.

[4]  L. Loeb,et al.  Mutagenesis by apurinic/apyrimidinic sites. , 1986, Annual review of genetics.

[5]  V. Skalski,et al.  Removal of anti-human immunodeficiency virus 2',3'-dideoxynucleoside monophosphates from DNA by a novel human cytosolic 3'-->5' exonuclease. , 1995, Biochemical pharmacology.

[6]  Samuel H. Wilson,et al.  Passing the baton in base excision repair , 2000, Nature Structural Biology.

[7]  T. Chou,et al.  Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. , 1996, AIDS research and human retroviruses.

[8]  M. Dante,et al.  Multifunctional yeast high-copy-number shuttle vectors. , 1992, Gene.

[9]  Kim Nasmyth,et al.  The B-type cyclin kinase inhibitor p40 SIC1 controls the G1 to S transition in S. cerevisiae , 1994, Cell.

[10]  B. Demple,et al.  Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. Lindahl,et al.  Suppression of spontaneous mutagenesis in human cells by DNA base excision-repair. , 2000, Mutation research.

[12]  Y. Matsumoto,et al.  Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. , 1995, Science.

[13]  A. Grollman,et al.  Incision Activity of Human Apurinic Endonuclease (Ape) at Abasic Site Analogs in DNA (*) , 1995, The Journal of Biological Chemistry.

[14]  B. Demple,et al.  Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Samuel H. Wilson,et al.  Substrate Binding by Human Apurinic/Apyrimidinic Endonuclease Indicates a Briggs-Haldane Mechanism* , 1997, The Journal of Biological Chemistry.

[16]  G. Lucchini,et al.  Cell cycle-dependent phosphorylation and dephosphorylation of the yeast DNA polymerase alpha-primase B subunit , 1995, Molecular and cellular biology.

[17]  C. Cazaux,et al.  Overexpression of DNA polymerase beta sensitizes mammalian cells to 2',3'-deoxycytidine and 3'-azido-3'-deoxythymidine. , 1997, Cancer research.

[18]  Dan J. Mazur,et al.  Identification and Expression of the TREX1 and TREX2 cDNA Sequences Encoding Mammalian 3′→5′ Exonucleases* , 1999, The Journal of Biological Chemistry.

[19]  Richard J Smeyne,et al.  The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Demple,et al.  Two distinct human DNA diesterases that hydrolyze 3'-blocking deoxyribose fragments from oxidized DNA. , 1991, Nucleic acids research.

[21]  K. Loeb,et al.  Significance of multiple mutations in cancer. , 2000, Carcinogenesis.

[22]  A. Tomkinson,et al.  Purification and Characterization of DNA Ligase III from Bovine Testes , 1995, The Journal of Biological Chemistry.

[23]  D. Pappin,et al.  Isolation of cDNA clones encoding an enzyme from bovine cells that repairs oxidative DNA damage in vitro: homology with bacterial repair enzymes. , 1991, Nucleic acids research.

[24]  T. Kunkel,et al.  The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations. , 1985, The Journal of biological chemistry.

[25]  A. Bhagwat,et al.  Delayed DNA joining at 3' mismatches by human DNA ligases. , 1999, Nucleic acids research.

[26]  Dan J. Mazur,et al.  Excision of 3′ Termini by the Trex1 and TREX2 3′→5′ Exonucleases , 2001, The Journal of Biological Chemistry.

[27]  R. Lloyd,et al.  Initiation of base excision repair: glycosylase mechanisms and structures. , 1999, Annual review of biochemistry.

[28]  J. Sgouros,et al.  A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein , 1999, The EMBO journal.

[29]  M. Kukhanova,et al.  A Novel Action of Human Apurinic/Apyrimidinic Endonuclease , 2000, The Journal of Biological Chemistry.